The OI Project
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Mission of the OI Project
The OI Project is a nonprofit organization committed to providing accurate information about Osteogenesis Imperfecta, with the ultimate goal of increasing awareness, advocating for those affected, and raising money to support patients and families living with this rare disease.
About Osteogenisis Imperfecta
Osteogenesis Imperfecta (OI), commonly known as brittle bone disease, is a group of genetic disorders that affect bone strength and structure. There are approximately 20 recognized types of OI, with Types I–IV being the most well-known. The severity of OI varies widely, from mild cases with only a few fractures over a lifetime to severe forms that can be life-threatening.
OI is primarily caused by mutations in genes responsible for producing type I collagen, a crucial protein for bone strength. In some cases, mutations in other genes that regulate bone formation and collagen processing also contribute to the disease. These genetic defects lead to increased bone fragility and often cause additional non-skeletal complications.
The condition affects approximately 1 in 12,000 to 15,000 babies worldwide, regardless of gender or ethnicity. Currently, between 25,000 and 50,000 people in the US are living with the condition. While there is currently no cure, various treatment options help manage symptoms and improve quality of life.​
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Education: The Facts
Overview on inheritance
Osteogenesis imperfecta (OI) is caused by mutations or defects in or related to genes that code for bone formation or a protein called collagen. This disorder is inherited in an autosomal dominant pattern, autosomal recessive pattern, or X-linked manner. Different types of mutations or inheritance patterns are responsible for the type of OI present in a person.
Dominant OI
Almost 90% of cases are dominant OI, which is when one of either the paternal or maternal gene responsible for or related to collagen production has mutated, and the abnormal gene produces defective or insufficient collagen which leads to OI despite the presence of an unmutated collagen gene. Dominant OI also encompasses a dominant inheritance pattern. This is when there is spontaneous mutation in the gametes, and the mutated genes are only in the child and neither of the parents. People who have dominant OI have a 50% chance of passing on OI to each child.
Recessive OI
10-15% of cases are caused by a recessive type of OI, which is when both the maternal and paternal gene involved in bone formation or collagen processing is mutated. People with recessive OI do not necessarily have parents with OI, but both parents carry one abnormal gene associated with OI and one dominant unmutated collagen gene that prevents them from exhibiting symptoms. When both parents carry this recessive mutated gene, there is a 25% chance that each child has OI.
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Siblings of people who have recessive OI have a 2 out of 3 chance of carrying one recessive abnormal gene and being carriers like their parents.
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If one parent has recessive OI (two recessive copies of the mutated gene), all of their children will carry a recessive mutated gene but will not have OI unless they have children with another dominant or recessive carrier of OI.
X-Linked OI
X-linked OI is extremely rare and is caused by a mutation in the MBTPS2 gene on the X chromosome in only type XIX OI. Because males have only one X chromosome, a single mutation in this gene is sufficient to cause OI, making it more common in males than females.
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Males with X-linked OI pass their affected X chromosome to all daughters, meaning all daughters will inherit the mutation, but they do not pass it to their sons.
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Female carriers, who have one mutated X chromosome, have a 50% chance of passing the mutation to each child. Sons who inherit the mutation will develop OI because they lack a second X chromosome to compensate, while daughters who inherit the mutation will be carriers unless they receive two mutated copies, one from each parent.
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In the rare case that both parents carry the mutation, there is a 25% chance that a daughter will inherit two mutated copies and have OI, a 50% chance that a child will inherit one mutated copy and either be a carrier (females) or affected (males), and a 25% chance that a child will inherit two normal copies and be unaffected.
Vision Problems
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Common refractive errors (nearsightedness, farsightedness, astigmatism) occur at similar rates as in the general population.
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More serious ocular conditions include:
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Glaucoma and retinal detachment, particularly in adults
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Blue sclerae is a hallmark of OI and may indicate corneal thinning
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Scleral thickness may be compromised in certain OI types
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Connective Tissue
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Fragile blood vessels and thin skin lead to easy bruising.
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Skin stiffness and reduced elasticity may increase scarring.
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Joint hyper flexibility is common, contributing to frequent:
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Sprains
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Dislocations (hips, shoulders, thumbs, elbows, ankles)
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Muscle weakness is often significant in moderate to severe OI.
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Flat feet are frequently seen, especially in Type I OI.
Endocrine System & Growth
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Short stature is common, particularly in moderate to severe cases, due to skeletal abnormalities such as bowed limbs and spinal deformities.
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Growth hormone levels are typically normal, but growth may still be impaired.
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Menstruation may be delayed in young women with OI.
Chronic Pain
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Acute pain from fractures or surgeries is common, but many individuals also experience chronic pain unrelated to fractures.
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Back pain may result from:
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Compression fractures of the spine
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Spinal deformities like scoliosis or kyphosis
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Some individuals report unexplained pain without clear structural abnormalities.
Spinal Issues
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Common spinal deformities include:
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Scoliosis (curved spine)
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Kyphosis (hunched back)
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Craniocervical junction abnormalities (which may lead to spinal cord compression)
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Joint & Mobility Concerns
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Joint hypermobility (loose joints) occurs due to defective collagen affecting ligaments.
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Muscle weakness due to a lack/deformity of collagen can contribute to joint instability and an increased risk of sprains.
Dental & Oral-Facial
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OI affects jaw growth and tooth development.
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About 50% of individuals with OI have dentinogenesis imperfecta (DI), where the dentin (the layer beneath enamel) is defective, leading to weak, discolored, and brittle teeth.
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Other common oral issues include:
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Impacted teeth
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Anterior and posterior open bites
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Crossbites
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underbite due to jaw misalignment
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Pulmonary (Respiratory) Issues
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Reduced lung capacity is the primary respiratory concern in OI.
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Other common respiratory complications:
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Ineffective cough and poor secretion clearance
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Airway diseases (e.g. asthma and sleep apnea)
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Low oxygen levels (hypoxia)
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Increased severity of preexisting lung conditions
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Contributing factors to pulmonary problems:
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Abnormalities of lung tissue and chest wall architecture (affecting chest size and shape)
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Limited mobility
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Gastrointestinal issues (e.g., constipation and reflux)
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Higher susceptibility to infections and allergies
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Hearing Impairment
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Around 50% of adults with OI develop hearing loss, typically emerging later in early adulthood
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Causes of hearing loss in OI:
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Bone quality and structural abnormalities in the middle and inner ear, including ossicle deformities
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Progressive degeneration of auditory structures
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Additional hearing-related symptoms:
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Tinnitus (ringing in the ears)
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Vertigo (dizziness and balance issues)
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Cardiovascular Complications
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A small percentage of adults with OI develop heart valve problems (e.g. mitral valve prolapse)
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Aortic dilation may occur in some cases.
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Hypertension (high blood pressure) is as common in adults with OI as in the general population.
Neurological Concerns
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Basilar impression (BI)—where the top of the cervical spine pushes into the base of the skull—can develop over time, particularly in individuals with severe OI, leading to brainstem compression.
Enlarged head circumference is often observed in infants and children with OI and may be associated with hydrocephalus (fluid buildup in the brain).
Overview on inheritance
The treatments for Osteogenesis Imperfecta (OI) vary widely, ranging from physical therapy and bone-strengthening medications to surgical interventions like bone realignment and fracture repair. While advancements in gene therapy and gene silencing show promise, these approaches are still experimental and not yet widely available. Overall, many of the current treatments are aimed at managing symptoms and improving quality of life, with ongoing research exploring more effective, long-term solutions.
Medications
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Bisphosphonates: Bisphosphonates are a class of drugs that help preserve bone density by inhibiting farnesyl pyrophosphate synthase, an enzyme necessary for producing molecules that allow osteoclasts to attach to bone and break it down. By blocking this process, osteoclasts detach from the bone surface, reducing bone resorption and helping maintain bone mass. While bone resorption is crucial for bone remodeling, calcium homeostasis, and repairing microdamage, slowing this process benefits individuals with osteogenesis imperfecta (OI) by improving bone density. Bisphosphonates are most effective during periods of growth, helping to increase bone mass and reduce fracture risk. Treatment can be started as soon as possible and typically continues until growth slows or stops, though children and adults with significant bone fragility, low bone density, or a high risk of fractures may remain on therapy longer.
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Bisphosphonates administered Intravenously (IV): Pamidronate and zoledronic acid are commonly administered intravenously in the treatment of OI. Pamidronate is administered every 3-4 months and zoledronic acid every 6 months.
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Bisphosphonates administered Orally: Alendronate, ibandronate, and risedronate are oral bisphosphonates that may be used in the treatment of OI. Alendronate is given once a week. Risedronate is given weekly or monthly depending on the dose. Ibandronate is given once a month.
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Growth hormone: Growth hormones stimulate bone formation by increasing osteoblast activity to potentially improve growth rate and bone density, especially in types I and IV. Growth hormones also have anabolic effects that promote muscle growth and strength and can aid in the growth of patients with mild OI who have short stature. Studies have shown that growth hormone treatments do not increase fracture risk in treated patients in the short term and can increase the rate of growth, bone turnover, and mineral content. There is little evidence about how they reduce fractures long-term, and, in comparison to bisphosphonates, their effect is minimal. Therefore, growth hormones are not currently a standard therapy for OI, though they can provide some benefits.
Surgeries
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Rodding: Rodding is a surgical procedure where metal rods are placed inside the long bones (such as the femur) to strengthen them and prevent fractures. The decision to do this is made on a case-by-case basis and mainly happens in children with moderate to severe forms of OI.
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Corrective surgery: There are other surgical measures to correct other defects from OI. There are certain dental procedures that can be done and other deformities, such as scoliosis, can be surgically corrected. This can occur among patients with all types of OI, from mild to severe
Physical therpaies
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Physical therapy: Patients with all types of OI, from mild to severe can go to physical therapy to strengthen muscles, improve mobility, and prevent deformities.
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Occupational therapy: Patients with all types of OI, typically those with more severe forms of OI can use occupational therapy to assist with daily activities and adapt to the challenges of OI.
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Assistive devices: Patients with all types of OI, typically those with more severe forms of OI can use devices such as wheelchairs, braces, and walkers. These devices are particularly common among patients with healing fractures.
Emerging therapies:
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Gene therapy: Research is ongoing to develop gene therapies to correct mutations causing OI that could potentially cure the disease. One example is gene editing using CRISPR-Cas9 technologies which would allow scientists to precisely cut and modify DNA sequences. This is still highly experimental, but is being tested both in-utero and postnatally, and future advancements could allow scientists to remove and replace faulty genes causing OI. Another treatment being researched is gene silencing, which can prevent a gene from being transcribed or translated, temporarily preventing the mutated gene from being expressed. This could help to reduce the severity of symptoms by preventing the production of defective collagen.
Stem cell therapy: Stem cell therapy is another up-and-coming treatment that could replace the faulty osteoblasts with stem cells that can correctly synthesize bone matrix.
Associated Genes
Osteogenesis Imperfecta (OI) is a genetic disorder primarily affecting the production or structure of type I collagen, the main protein forming the structural framework of bone. There are several types of OI, classified based on the severity of the condition and the underlying genetic defect. While the most common classification focuses on types I through V, there are up to 19 recognized types which are determined by the specific gene affected and the resulting physical deformities. The majority of OI cases (about 90%) are caused by mutations in the COL1A1 and COL1A2 genes, which lead to either reduced quantity or abnormal structure of type I collagen. However, mutations in other genes involved in collagen processing or bone formation can also cause rarer forms of OI. These genetic mutations result in bones that are brittle and fracture easily compared to those of individuals with normal collagen production. The severity of OI ranges from mild cases with few fractures to severe cases that can be lethal in the perinatal period. Types I through IV represent this spectrum, with Type I being the mildest and most common, and Type II being the most severe and often lethal. Type V has distinct features that set it apart from the others.
Type I: Type I OI is the mildest and most common form of the disease, accounting for about 50–60% of all cases. Approximately 0.004% of the global population is affected by this type however that number could be higher due to undiscovered mild cases Type I will often result in a low quantity of bone-related injuries throughout a patient's life span and is sometimes aligned with an “invisible disorder” because it is not apparent to the casual observer. Type I is also an outlier because it is the only instance where the affected individual has normal type I collagen; however, it is generally half the normal amount of that which would be found in an unaffected individual. Genetically, this condition is autosomal dominant, meaning it is found in a numbered chromosome and not a sex chromosome, so it affects both genders equally. It is a dominant trait, so only one copy is necessary to affect the person. In Type I OI, there are mutations in the COL1A1 gene, or sometimes the COL1A2 gene, causing it to fail to produce viable mRNA for procollagen—the precursor to collagen. Although in Type I, the resulting molecule may be structurally normal, it functions improperly, leading to a shortage of collagen. The symptoms, like any disorder, can vary from person to person, but they are generally consistent with pre-pubescent and post-pubescent breaks, abnormal tint to the sclera, easy bruising, curved/compressed spine, loose joints, muscle weakness, and lax ligaments, which can all be attributed to the collagen deficiency. Those affected by Type I OI typically have a normal life expectancy and can lead relatively normal lives. However, they may experience difficulty with sports or physical activity due to brittle bones and loose ligaments. Scoliosis is sometimes associated with the condition, and hearing loss may develop later in life.
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Type II: Whereas Type I Osteogenesis Imperfecta affects around 4.7 in 100,000 people, Type II is much rarer, affecting 1.4 in 100,000 live births. It is the most severe condition of the disease, it is typically diagnosed 18-24 weeks into pregnancy, with virtually all cases that make it to term resulting in death just weeks after birth. Type II OI can be autosomal dominant or autosomal recessive (in much rarer cases) depending on the affected genes. Autosomal dominant Type II OI is when there are mutations in the COL1A1 or COL1A2 resulting in the disruption of assembly of collagen molecules leading to the production of abnormal type I collagen. When abnormal collagen is present instead of a regular amount of normal collagen, it results in extremely brittle bones, issues with connective tissues, and serious (and usually fatal in this case) health problems. Research has found that other genes, such as CRTAP and LEPRE1, are autosomal recessive mutations that can cause Type II OI but are much rarer than mutations of the COL1A1 or COL1A2 gene. CRTAP and LEPRE1 mutations indirectly affect collagen by impairing protein-protein interactions during collagen biosynthesis and assembly, resulting in defective bone matrix formation and severe bone fragility. The general symptoms of peritoneal OI (Type II) are demonstrated through extreme bone brittleness, delayed skull ossification (change from connective tissue into bone), blue sclera, underdeveloped lungs, and severe bone deformities. However, the deformities can be further classified through subtypes A, B, and C, which are distinguished by radiological differences (findings observed with medical technology). Patients with OI Type IIA typically present with broad ribs showing multiple fractures, continuous beading along the ribs, and severe under-modeling of the femur. In contrast, OI Type IIB is characterized by normal or thin ribs with a few fractures, discontinuous rib beading, and mild femoral under-modeling. OI Type IIC features ribs of variable thickness with discontinuous beading, malformed scapulae, and ischia, as well as long bones with thin shafts and expanded metaphyses. Type IIA is caused by mutations in the COL1A1 and COL1A2 genes, Type IIB is the same as well as mutations in the CRTAP, P3H1, and PPIB genes, and Type IIC is much rarer and known to be caused only by the MESD gene which impairs Wnt signaling, in turn affecting bone regeneration and production. In all cases of Type II OI, the bones are so brittle that the fetus sustains multiple fractures before birth. Combined with underdeveloped lungs that cause severe respiratory complications, this results in preterm death or death shortly after birth.
Type III: Type III OI is the most severe type of the disease among those who survive the neonatal period. Bones are extremely brittle, resulting in fractures that occur before birth. Some of these fractures may heal in utero and appear as healed injuries on postnatal X-rays, while others may still be present at birth. This is also an autosomal dominant inheritance pattern, and collagen production is abnormal and reduced. Type III OI is most often caused by mutations in the COL1A1 or COL1A2 gene which hinder the proper folding and assembly of collagen molecules. Additionally, mutations in genes such as CRTAP, LEPRE1 (P3H1), PPIB, FKBP10, SERPINH1, SERPINF1, and WNT1 can also cause Type III OI, often in an autosomal recessive pattern. As in OI Type II, the type I collagen produced is abnormal, and this, combined with a deficiency in collagen and other gene defects, leads to increased molecular spacing and weakened molecular adhesion in bone, resulting in extreme brittleness and deformities. However, Type II OI is much more severe than Type III despite genetic defects being relatively similar. This is because mutations in COL1A1 or COL1A2 genes in Type III are often less disruptive to overall collagen structure than in Type II. The physical deformities often associated with this type include blue sclera, extreme bone fragility, skeletal deformities, loose joints, poor muscle development in the limbs, triangular face, barrel-shaped rib cage, curved spine, vertebral compression or collapse, scoliosis, and extremely short stature. Life expectancy in Type III is much less definitive than in Type II and can range from death in early childhood due to respiratory issues to a nearly normal life span. People with Type III OI face severe mobility restrictions with most affected individuals requiring a walker or wheelchair. Only a small percentage of individuals are able to perform tasks such as walking while carrying an object or using stairs with a railing. They tend to have reduced gross motor function, especially when standing or transferring positions, along with lower muscle strength in both the upper and lower limbs compared to those with milder forms of OI. Additionally, decreased chest volume, chronic bronchitis, and asthma are common, which can contribute to restrictive pulmonary disorders.
Type IV: Type IV Osteogenesis Imperfecta (OI) is a moderately severe form of the disorder (more serious than Type I, but less severe than Type III) which is autosomal dominant. While it shares some similarities with Type I, it is primarily distinguished by its clinical manifestations. Unlike individuals with Type I OI, who produce a normal structure of type I collagen, those with Type IV, like in Types II and III, exhibit both quantitative and qualitative abnormalities. This means they produce a reduced amount of structurally abnormal type I collagen, which compromises bone strength. The underlying structural defects in Type IV OI typically occur in the COL1A1 or COL1A2 genes, where mutations disrupt the formation of the collagen triple helix, impairing collagen production which weakens bones and connective tissue. Research has identified several other genes that can be affected in Type IV OI besides COL1A1 and COL1A2. These include CRTAP, FKBP10, SP7, SERPINF1, WNT1, and TMEM38B. Mutations in these genes can lead to OI phenotypes that may be clinically similar to or indistinguishable from Type IV OI caused by COL1A1 or COL1A2 mutations. Type IV Osteogenesis Imperfecta is characterized by moderate bone fragility, bone deformities, and a shorter-than-average stature. Common symptoms include fractures that may occur before birth or during childhood, normal-colored sclerae, vertebral compression, a barrel-shaped rib cage, and possible hearing loss or dental issues such as brittle teeth. Type IV has two subtypes: Type IVA and Type IVB. The primary distinction between them is the presence of dentinogenesis imperfecta (DI), a condition affecting tooth strength and color. In Type IVA, individuals may experience DI, leading to weak, discolored teeth. In contrast, Type IVB does not involve DI, meaning tooth strength and color remain unaffected. Both subtypes share the same general skeletal symptoms but differ in their impact on dental health. People with type IV generally live into adulthood but may have a slightly shortened lifespan. Individuals with Type IV Osteogenesis Imperfecta (OI) face several restrictions, including mild to moderate bone deformities, limited mobility, increased susceptibility to fractures, and potential for scoliosis and joint problems. These limitations can impact daily activities and quality of life, but with proper medical management and rehabilitation, many people with Type IV OI can achieve good functional outcomes and lead relatively independent lives.
Type V: Type V OI is autosomal dominant and similar to Type IV in appearance and symptoms. Type V is much rarer than any of the previously mentioned forms of the disease however, it is important to discuss due to the genetic differences. Types I-IV are caused by mutations in the COL1A1 and COL1A2 genes (with other gene defects having added effects). However, Type V results from a specific mutation in the IFITM5 gene. This mutation alters the BRIL protein's function, leading to abnormal bone formation and remodeling. Although not directly caused by collagen gene mutations, Type V OI still impacts collagen-related processes, including decreased COL1A1 transcripts, reduced type I collagen protein production and secretion, and altered collagen matrix structure. These effects, combined with increased mineralization in osteoblasts, contribute to the unique clinical features of Type V OI. These features include hyperplastic callus formation (enlarged, thickened areas at fracture sites), calcification of the interosseous membrane between the radius and ulna (limiting forearm rotation), anterior radial head dislocation (affecting elbow joint movement), and radio dense metaphyseal bands near growth plates (visible on X-rays as thickened areas). These set Type V apart from other forms of OI and can aid in its diagnosis. In addition to its unique traits, Type V OI lacks some standard features seen in different types, such as blue sclerae (typical in Types I and III) and dentinogenesis imperfecta (seen in Types IVA and VI). Other notable, and more common, characteristics include scoliosis, loose ligaments similar to Type IV, and distinct features such as a triangular face. While life expectancy is not typically shortened compared to the general population, mobility is often impacted by the recurrent fractures, joint contractures, and spinal deformities induced by Type V OI causing assistive devices to be necessary in some cases. Approximately 54% of patients develop vertebral compression fractures, and 50% experience severe scoliosis, which can contribute to respiratory limitations or reduced functional mobility.
Types VI through XVIII of Osteogenesis Imperfecta (OI) represent rarer forms of the disorder, typically caused by mutations in genes other than COL1A1 and COL1A2. These types can often be classified as subtypes of the classic Types I-IV due to clinical similarities. Type VI, caused by mutations in the SERPINF1 gene, resembles Type IV OI but is distinguished by a "fish-scale" appearance of bone under microscope, curved spine, and progressive symptoms starting between 4-18 months of age. It features white or faintly blue sclerae and no dentinogenesis imperfecta. Type VII, resulting from CRTAP gene mutations, is similar in severity to Types II and III, characterized by white sclera, small stature, and short humerus and femur. Types VIII and IX, caused by mutations in LEPRE1 and PPIB genes respectively, are generally severe and similar to Types II and III. These types, along with Type VII, form the CRTAP/LEPRE1/PPIB group, which is crucial for proper collagen modification. Information on Types X through XVIII is less abundant, but they generally range from moderate to severe in their manifestations. Many of these rarer types are clinically indistinguishable from the classic Types I-IV. Their inheritance patterns vary, with some types showing autosomal recessive inheritance. As research in this field progresses, more specific information about these rarer types is likely to emerge, providing a clearer understanding of their genetic causes, clinical presentations, and potential treatment approaches. Each of these types is classified as moderate to severe. Although research is limited, life expectancy is generally expected to be relatively normal; however, complications such as respiratory issues can impact this. Individuals may experience reduced mobility requiring assistive devices, increased risk of fractures, and potential skeletal deformities depending on the gene affected and the severity of the disease.
Type XIX: Each of the previously mentioned types of OI occurs due to mutations in genes located on autosomal (numbered) chromosomes, meaning the likelihood of being affected is equal for both males and females. However, Type XIX is caused by a mutation in the MBTPS2 gene which is a sex chromosome found on the X chromosomes. It is the only known type of OI inherited in an X-linked recessive pattern, meaning it primarily affects males. This gene encodes a protein involved in regulated intramembrane proteolysis, a process critical for healthy bone formation. Disruption of this process leads to the characteristic bone fragility and other symptoms of OI. Clinically, Type XIX shares some features with other severe forms of OI, such as frequent fractures and skeletal deformities. However, its inheritance pattern and genetic cause set it apart from other types. Females with one mutated copy of the MBTPS2 gene are typically unaffected carriers, while males with the mutation exhibit the full spectrum of symptoms. The primary symptoms of Type XIX include prenatal fractures, generalized osteopenia (low bone mineral density), and severe short stature in adulthood. Because of how rare this type is, data is extremely limited. However, life expectancy is thought to be slightly below average. Type XIX is considered a severe form of OI, marked by extremely short stature and pronounced bone deformities that significantly impact mobility and overall quality of life.
Associated Genes
Osteogenesis imperfecta (OI) is caused by mutations or defects in or related to genes that code for bone formation or a protein called collagen. This disorder is inherited in an autosomal dominant pattern, autosomal recessive pattern, or x-linked manner. Different types of mutations or inheritance patterns are responsible for the type of OI present in a person.
COL1A1 gene and the COL1A2 gene: COL1A1 mutations are more common than COL1A2 mutations. Mutations in these genes are most commonly responsible for types I through IV. These genes normally function by forming the body’s triple-stranded procollagen molecules for type I collagen. In normal type I collagen, two of these chains are pro-a1(I) and produced from the COL1A1 gene, and one chain is pro-α2(I) which is produced from the COL1A2 gene. These chains are coiled around each other to form a triple helix. Then these chains are synthesized to create mature collagen which arrange themselves into long fibrils. These fibrils form cross links with other collagen fibrils to create strong type I collagen fibers. Much of this collagen is present in cells' extracellular matrix (ECM). Collagen deficiency and deformity resulting in mutations in these genes creates a weak and disorganized ECM. This results in impaired bone mineralization, reduced mechanical strength, and disrupted cell signaling, ultimately causing fragile bones and connective tissue defects. Within these defects, mutations can either cause quantitative deficiencies in type I collagen, or qualitative defects. A secondary structure in each strand in type I collagen protein is the helical domain which consists of glycine (and often proline and hydroxyproline). Often, errors in the glycine substitutions in this domain due to gene defects lead to errors with chain association (the way the triple strands align with each other) and protein foldings—errors in the α1(I) strands are associated with more severe phenotypes of OI, and errors in the α2(I) strands are less severe—causing OI. This disruption of normal collagen production or function by mutations in these genes account for a wide range of symptoms, with type I being relatively mild and type II being fatal. These two genes are primarily inherited in an autosomal dominant pattern.
IFITM5 gene: Mutations in this gene are most commonly associated with OI type V. This gene is involved in bone formation and maturation by encoding for the membrane protein BRIL, a protein in bone-forming cells that plays a role in bone mineralization. The mutation of this gene leads to the inclusion of extra amino acids of the BRIL protein. While type I collagen is structurally normal, this mutation alters the proteins localization or interactions with other bone-regulating proteins, contributing to abnormal bone formation prenatally and defective bone remodeling postnatally. It can also cause excessive bone formation and mineralization defects. This mutation is inherited in an autosomal dominant pattern.
SERPINF1 gene: Mutations in the SERPINF1 gene are most commonly associated with OI type VI. This gene encodes pigment epithelium-derived factor (PEDF), a protein that plays a role in bone formation by regulating osteoblast (bone-forming cells) and osteoclast (bone-resorbing cells) differentiation and bone mineralization. In OI, there is homozygous deletion of nucleotides which results in a change in the amino acid sequence. This frame-shift mutation usually leads to a premature stop codon which truncates the PEDF protein and prevents it from being functional. Although type I collagen synthesis is unaffected, the deficiency of PEDF disturbs the equilibrium between bone formation and resorption. Ultimately this mutation results in low bone mass with defective bone mineralization, increased bone fragility, irregular bone matrix organization, and ongoing progressive skeletal deformities. This mutation, being homozygous, is inherited in an autosomal recessive pattern.
CRTAP gene: Mutations in this gene are most commonly associated with OI type VII. This gene encodes cartilage-associated protein (CRTAP) and is known to work alongside the LEPRE1 and PPIB genes to hydroxylate proline residues, an abundant amino acid in the strands of type I collagen. This hydroxylation occurs as the prolyl 3-hydroxylation complex—in which the CRTAP protein acts as the chaperone protein to help folding—and is a crucial modification of collagen. There are a few possible CRTAP mutations that include nonsense mutations which is when a nucleotide in the DNA sequence is changed into a stop codon and the protein is truncated; missense mutations that alter amino acid composition; frameshift mutations from insertions or deletions that disrupt the reading frame and normal sequence of codons often leading to a non-functional protein; or splicing defects that disrupt mRNA processing. These mutations result in defective collagen post-translational modifications, leading to structurally unstable collagen fibers. While the quantity of type I collagen production is unaffected, the improperly modified collagen is structurally defective. The deformed collagen disrupts extracellular matrix stability, contributing to severe bone fragility, growth deficiency, and joint laxity. This mutation is inherited in an autosomal recessive pattern.
LEPRE1 gene: The mutation and outcomes in LEPRE1 mutations are very similar to the CRTAP gene. Mutations in this gene are most commonly associated with OI type VIII. This gene encodes prolyl 3-hydroxylase 1 (P3H1), the enzyme that works alongside CRTAP and PPIB to catalyze the hydroxylation of the specific proline residues in type I collagen. This modification, known as prolyl 3-hydroxylation, is essential for proper collagen folding and stability. Mutations in LEPRE1 can include nonsense mutations leading to early stop codons, missense mutations that alter amino acid composition, frameshift mutations from insertions or deletions, or splicing defects that disrupt mRNA processing. The absence or dysfunction of P3H1 results in improperly modified collagen, leading to disorganized collagen fibrils and a structurally weak extracellular matrix. While the overall quantity of type I collagen remains unchanged, its defective post-translational modification contributes to severe bone fragility, growth impairment, and joint laxity. This mutation is inherited in an autosomal recessive pattern.
PPIB gene: The mutation and outcomes in PPIB mutations is very similar to the CRTAP and LEPRE1 genes. Mutations in this gene are most commonly associated with OI type IX. This gene encodes peptidyl-prolyl isomerase B (PPIB), an enzyme that plays a critical role in the prolyl 3-hydroxylation complex, working alongside CRTAP and LEPRE1. PPIB facilitates the proper folding of collagen molecules by catalyzing the cis-trans isomerization of proline residues, an essential step in collagen's post-translational modification. Mutations in the PPIB gene can include early stop codons, missense mutations, frameshift mutations, or splicing defects. These mutations impair collagen hydroxylation, leading to the production of defective collagen fibers. While the quantity of type I collagen is unaffected, the collagen produced is structurally compromised, disrupting the extracellular matrix and leading to weakened bone structure, fragility, and growth deficiencies. The condition is inherited in an autosomal recessive pattern.
SERPINH1 gene: Mutations in the SERPINH1 gene are most commonly associated with OI type X. This gene encodes heat shock protein 47 (HSP47), a chaperone protein in the endoplasmic reticulum that is essential for the proper folding, assembly, and secretion of collagen molecules, particularly type I collagen. HSP47 interacts with collagen in the endoplasmic reticulum, ensuring its correct folding and preventing the accumulation of misfolded collagen. Mutations in the SERPINH1 gene often lead to homozygous deletions or point mutations, resulting in a defective or truncated HSP47 protein, which impairs collagen processing. Although the quantity of type I collagen synthesized may remain unaffected, the collagen produced is improperly folded, leading to defective collagen fibril formation. This disrupts the extracellular matrix, resulting in low bone mass, increased bone fragility, and progressive skeletal deformities. This mutation is inherited in an autosomal recessive pattern.
FKBP10 gene: Mutations in the FKBP10 gene are most commonly associated with OI type XI. This gene encodes FKBP65 (Fibronectin type III domain-containing protein), a protein in the rough endoplasmic reticulum that functions as a chaperone for collagen molecules, assisting in their proper folding and stability. FKBP10 is involved in collagen synthesis and plays a key role in bone mineralization and maintaining the integrity of the extracellular matrix. In OI, mutations in the FKBP10 gene, which can involve deletions, point mutations, or missense mutations, lead to the production of a defective FKBP65 protein. This results in improper collagen folding and destabilization of collagen fibrils. While the quantity of type I collagen production may remain normal, the collagen produced is structurally compromised. The mutation leads to disrupted bone mineralization, increased bone fragility, and progressive skeletal deformities. This mutation is inherited in an autosomal recessive pattern.
SP7 gene: Mutations in the SP7 gene are most commonly associated with OI type XII. This gene encodes osterix (OSX), a transcription factor that plays a crucial role in osteoblast differentiation and the regulation of bone formation. Osterix is essential for the maturation of osteoblasts and the synthesis of bone matrix proteins, including type I collagen. In OI, mutations in the SP7 gene, which can include missense mutations, deletions, or frame-shift mutations, lead to impaired osterix function. This disrupts the ability of osteoblasts to properly differentiate and form bone tissue. While type I collagen synthesis may still occur, the formation and organization of the bone matrix is severely affected, leading to reduced bone density, increased bone fragility, and progressive skeletal deformities. This mutation is inherited in an autosomal dominant pattern.
BMP1 gene: Mutations in the BMP1 gene are most commonly associated with OI type XIII. This gene encodes bone morphogenetic protein 1 (BMP1), a metalloprotease enzyme that is essential for the maturation of collagen by cleaving the terminal propeptides off of type I collagen strands. This is a critical step in collagen fibril formation and the stabilization of the bone matrix. Mutations in the BMP1 gene, which may include missense mutations, deletions, or frameshift mutations, result in a defective BMP1 enzyme that is unable to effectively process collagen precursors by allowing self-assembly into fibrils. Although the quantity of type I collagen synthesis remains normal, the defective processing leads to the formation of abnormal collagen fibrils, making it a qualitative defect and disrupting the structural integrity of bone and the extracellular matrix. This results in low bone mass, increased bone fragility, and progressive skeletal deformities. This mutation is inherited in an autosomal dominant pattern.
WNT1 gene: Mutations in the WNT1 gene are most commonly associated with OI type XV. This gene encodes wingless-type MMTV integration site family member 1 (Wnt1), a key protein involved in the Wnt signaling pathway, which plays a crucial role in bone development, osteoblast differentiation, and bone homeostasis. Wnt1 signaling is essential for the regulation of osteoblast activity and the maintenance of bone mass and strength. In OI, homozygous or heterozygous mutations in WNT1 lead to impaired Wnt signaling, which disrupts osteoblast function and impairs bone formation and remodeling. These mutations can include missense mutations, frameshift mutations, or deletions, which result in reduced or dysfunctional Wnt1 protein. While type I collagen synthesis remains unaffected, the lack of proper Wnt signaling leads to defective bone mineralization, decreased bone mass, and increased skeletal fragility. Homozygous mutations typically lead to a more severe autosomal recessive form of OI, whereas heterozygous mutations are linked to early-onset osteoporosis.
CREB3L1 gene: Mutations in the CREB3L1 gene are most commonly associated with OI type XVI. This gene encodes cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1), a transcription factor that plays a crucial role in osteoblast differentiation and collagen synthesis regulation. CREB3L1 is essential for the proper expression of COL1A1 and COL1A2, the genes encoding type I collagen, which is the primary structural protein in bone. In OI, homozygous mutations in CREB3L1 lead to reduced transcription of type I collagen genes, impairing collagen production and extracellular matrix formation. These mutations often result in nonsense or frameshift mutations, which produce a nonfunctional or truncated protein. This defect disrupts normal bone matrix organization, leading to severely weakened bones, impaired mineralization, and skeletal fragility. Unlike other forms of OI, which may involve structurally abnormal collagen, OI type XVI is primarily characterized by a significant reduction in collagen production. This mutation follows an autosomal recessive inheritance pattern.
SPARC gene: Mutations in the SPARC gene are most commonly associated with OI type XVII. This gene encodes cysteine-rich acidic matrix-associated protein (SPARC), also known as osteonectin, a non-collagenous matrix protein that plays a crucial role in bone mineralization, extracellular matrix organization, and osteoblast function. SPARC is essential for binding and regulating collagen fibril formation and interacting with calcium to facilitate bone mineral deposition. In OI, homozygous or compound heterozygous mutations in SPARC lead to defective collagen-binding and abnormal bone matrix mineralization. These mutations can include missense, nonsense, or frameshift mutations, resulting in a nonfunctional or reduced SPARC protein. Although type I collagen synthesis remains unaffected, the loss of SPARC function disrupts collagen organization and bone mineralization, leading to low bone mass, increased skeletal fragility, and severe bone deformities. This mutation follows an autosomal recessive inheritance pattern.
FAM46A gene: Mutations in the FAM46A gene are most commonly associated with OI type XVIII. This gene encodes a protein called TENT5A (Terminal Nucleotidyltransferase 5A), a nucleotidyltransferase that plays a role in bone development, osteoblast differentiation, and extracellular matrix organization. While its exact function in bone formation is not fully understood, FAM46A is believed to regulate osteoblast proliferation and type I collagen production. In OI, homozygous or compound heterozygous mutations in FAM46A lead to impaired osteoblast activity and reduced bone matrix deposition. These mutations often include missense, nonsense, or frameshift mutations, resulting in a nonfunctional or truncated FAM46A protein. While type I collagen structure remains normal, defective osteoblast function leads to decreased collagen synthesis, poor bone mineralization, and severe skeletal fragility. This mutation follows an autosomal recessive inheritance pattern.
MBTPS2 gene: Mutations in the MBTPS2 gene are most commonly associated with OI type XIX. This gene encodes site-2 protease (S2P), a membrane-bound zinc metalloprotease that plays a critical role in regulated intramembrane proteolysis (RIP). S2P cleaves and activates transcription factors (ex. SREBPs & ATF6), which are essential for cholesterol homeostasis, lipid metabolism, and the cellular response to endoplasmic reticulum stress. These processes are necessary for proper osteoblast differentiation, bone mineralization, and matrix organization. In OI, hemizygous (where an individual has only one copy of a gene, usually in male genes on the x chromosome) mutations in MBTPS2 impair the function of S2P, leading to dysregulation of lipid and cholesterol homeostasis, which disrupts osteoblast function and bone matrix formation. Mutations can include missense, nonsense, or frameshift mutations, leading to a nonfunctional or truncated S2P protein. Although type I collagen synthesis may remain unaffected, this disruption in osteoblast activity causes abnormal bone mineralization, low bone mass, and increased skeletal fragility. As MBTPS2 is X-linked, this form of OI follows an X-linked recessive inheritance pattern, primarily affecting males.
MESD gene: Mutations in the MESD gene are most common associated with OI type XX. This gene encodes Mesoderm development LRP chaperon (MESD), a chaperone protein required for the proper folding and trafficking of LRP5 and LRP6, key co-receptors in the Wnt signaling pathway, which is essential for osteoblast differentiation and bone formation. In OI, homozygous or compound heterozygous mutations in MESD can include missense, nonsense, or frameshift mutations, leading to a loss of MESD function. This disruption impairs Wnt signaling, which in turn affects osteoblast proliferation, differentiation, and bone matrix production. While type I collagen synthesis remains unaffected, the inability to properly activate Wnt signaling leads to severe bone fragility, delayed skeletal development, and profound osteopenia. Mutations in MESD follow an autosomal recessive inheritance pattern.
KDELR2 gene: Mutations in the KDELR2 gene are associated with OI type XXI. This gene encodes KDEL Endoplasmic Reticulum Protein Retention Receptor 2 (KDELR2), which plays a crucial role in the retrieval and retention of chaperone proteins within the endoplasmic reticulum (ER), ensuring proper protein folding and trafficking. In OI, homozygous or compound heterozygous mutations in KDELR2 can lead to impaired ER function, disrupting the proper folding and secretion of type I collagen. This defect results in misfolded collagen molecules, affecting bone matrix organization, mineralization, and overall bone strength. Individuals with KDELR2 mutations experience severe bone fragility, frequent fractures, and skeletal deformities. This mutation follows an autosomal recessive inheritance pattern.
CCDC134 gene: Mutations in the CCDC134 gene are associated with OI type XXII. This gene encodes Coiled-Coil Domain-Containing Protein 134 (CCDC134), a secreted protein involved in cell signaling pathways that regulate osteoblast function and bone homeostasis. In OI, homozygous or compound heterozygous mutations in CCDC134 can impair its normal function, leading to defective osteoblast differentiation and extracellular matrix production. While type I collagen production may be indirectly affected, the primary consequence of CCDC134 mutations is disrupted bone remodeling and mineralization, resulting in low bone mass, severe skeletal deformities, and increased susceptibility to fractures. Mutations in this gene follow an autosomal recessive inheritance pattern.
PHLDB1 gene: Mutations in the PHLDB1 gene are associated with OI type XXIII. This gene encodes Pleckstrin Homology Like Domain-Containing Protein 1 (PHLDB1), which is involved in cell adhesion, cytoskeletal organization, and intracellular signaling—processes that are critical for osteoblast function and bone formation. In OI, homozygous or compound heterozygous mutations in PHLDB1 can impair osteoblast differentiation and matrix production, leading to defective bone mineralization and reduced bone strength. Although the exact mechanism by which PHLDB1 mutations contribute to OI is still being studied, affected individuals experience severe bone fragility, frequent fractures, and skeletal deformities. This mutation follows an autosomal recessive inheritance pattern.
PLOD2 gene: Mutations in the PLOD2 gene are associated with OI type XXIV. This gene encodes Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2), an enzyme responsible for lysyl hydroxylation, a key modification required for proper collagen cross-linking and extracellular matrix stability. In OI, homozygous or compound heterozygous mutations in PLOD2 result in abnormal collagen cross-linking, leading to weakened collagen fibers, impaired bone matrix organization, and deficient bone strength. Affected individuals present with severe bone fragility, frequent fractures, and skeletal deformities due to compromised collagen integrity. This mutation follows an autosomal recessive inheritance pattern.
TMEM38B gene: Mutations in the TMEM38B gene are most commonly associated with OI type XIV. This gene encodes trimeric intracellular cation channel type B (TRIC-B), a channel protein that plays a role in calcium ion homeostasis within osteoblasts by facilitating the release of calcium ions from the endoplasmic reticulum which is essential for collagen production, bone mineralization, and overall bone matrix organization. In OI, homozygous or compound heterozygous mutations in TMEM38B can include deletions, missense mutations, or frameshift mutations, leading to a loss of functional TRIC-B. This disruption in calcium signaling impairs osteoblast function, affecting proper bone formation and mineralization. Although type I collagen synthesis is unaffected, defective calcium regulation leads to abnormal bone matrix organization, reduced bone strength, and increased fragility. Ultimately, this mutation results in low bone mass, severe bone deformities, and frequent fractures. This mutation follows an autosomal recessive inheritance pattern.
Where donations go
Shriners Children's Hospital in Montreal, Canada
Shriners Hospitals is an international pediatric health care system that includes hospitals, clinics, ambulatory surgery centers, and global outreach programs across 38 locations. The first Shriners hospital opened in 1922 in Shreveport, Louisiana, in response to the polio epidemic that plagued the United States during the 1910s. As it became clear that many children were not receiving the care they needed, the Shriners established a children's hospital to help meet this urgent need.
Shriners Children’s is committed to providing its distinctive, patient-focused, comprehensive care to as many children as possible, regardless of where they live, which is why it established itself as a non-profit organization. (A non-profit is when 100% of the funds go back into supporting the organization rather than to benefit owners and shareholders.) At Shriners approximately 80% of all expenses go into patient care, research, and education and the remaining 20% is spent on operational or administrative costs. Additionally, Shriners Children’s offers specialized pediatric care at all its locations regardless of a family’s insurance status or ability to pay. Patients are never billed, and even if insurance is used, families are not responsible for any out-of-pocket costs.
Shriners Children’s provides support for a wide range of conditions, including orthopedic issues, burn injuries, craniofacial abnormalities, spinal conditions and spinal cord injuries, as well as colorectal, gastrointestinal, and sports-related concerns. All profits from the OI Project will be directed towards the Shriners Hospitals for Children in Canada because Shriners Children's in Montreal is renowned for its expertise in treating Osteogenesis Imperfecta (OI). The hospital offers comprehensive care for children with OI, including specialized orthopedic treatments, rehabilitation services, and cutting-edge research. Their multidisciplinary team provides tailored treatment plans, which may include bisphosphonate therapy to increase bone density, surgical interventions to correct deformities, and physical therapy to improve mobility and strength. The hospital's research center has made significant contributions to understanding and treating OI, developing innovative approaches and enrolling patients in clinical trials that have improved the quality of life for many patients. With bilingual services in English and French, Shriners Children's in Montreal serves as a crucial resource for OI patients and their families, not only from across Canada but also internationally, offering hope and advanced care for this complex condition.