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76-416: SP7 may refer to : Sp7 transcription factor , a human gene 2771 Polzunov (1978 SP7), a Main-belt Asteroid discovered on September 26, 1978 S.A.R.A. SP7, a chassis of a racing car used at the 1928 24 Hours of Le Mans [REDACTED] Topics referred to by the same term This disambiguation page lists articles associated with the same title formed as
152-404: A Norwegian study of fifteen people with OI emphasized that they feel doctors should consider the whole patient and not just fracture rates. Bone fractures are treated in individuals with osteogenesis imperfecta in much the same way as they are treated in the general population—OI bone heals at the same rate as non-OI bone. A greater emphasis is placed on using lightweight materials to immobilize
228-647: A bulge in the collagen complex , which in turn influences both the molecular nanomechanics and the interaction between molecules , which are both compromised. Depending on both the location of the substitution and the amino acid being used instead, different effects are seen which account for the type diversity in OI despite the same two collagen genes being responsible for most cases. Replacements of glycine with serine or cysteine are seen less often in fatal type II OI, while replacements with valine , aspartic acid , glutamic acid , or arginine are seen more often. At
304-433: A combination of both ("mixed"). If hearing loss does not occur by age 50, it is significantly less likely to occur in the years afterwards. Mixed hearing loss is most common among those with OI of all age groups, while conductive hearing loss is most likely to affect older people, with sensorineural hearing loss most likely to affect children. Although relatively rare, OI-related hearing loss can also begin in childhood; in
380-626: A finding that osteogenesis imperfecta was the true cause of a child's fractures, leading to lawsuits seeking redress such as Alice Velasquez, et al. v. United States . Other differential diagnoses include rickets and osteomalacia , both caused by malnutrition , as well as rare skeletal syndromes such as Bruck syndrome , hypophosphatasia , geroderma osteodysplasticum , and Ehlers–Danlos syndrome . Various forms of osteoporosis , such as iatrogenic osteoporosis, idiopathic juvenile osteoporosis , disuse osteoporosis and exercise-related osteoporosis should also be considered as explanations when OI
456-426: A high enough quality. Clinical differentiation between types III and IV is not always simple, and is further confounded by the fact that an untreated adult with type IV may have worse symptoms than a treated adult with type III; features only found in type III are its progressively deforming nature and the presence of a face with a "triangular" appearance. Another differentiating factor between type III and IV
532-426: A larger scale, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone is altered, causing brittleness. Bone fractures occur because the stress state within collagen fibrils is altered at the locations of mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate loads because the homogeneous stress state normally found in healthy collagen fibrils
608-805: A letter–number combination. If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=SP7&oldid=1125010091 " Category : Letter–number combination disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Sp7 transcription factor 170574 ENSG00000170374 ENSMUSG00000060284 Q8TDD2 Q8VI67 NM_001173467 NM_001300837 NM_152860 NM_130458 NM_001348205 NP_001287766.1 NP_001166938 NP_001287766 NP_690599 NP_569725 NP_001335134 Transcription factor Sp7 , also called Osterix (Osx) ,
684-414: A study of 37 families, a 1.3% chance was found that OI recurs in multiple siblings born to two unaffected parents—this is a much higher rate than would be expected if all such recurrences were de novo . The cause is genetic mosaicism ; that is, some of, or most of, the germ cells of one parent have a dominant form of OI, but not enough of their somatic cells do to cause symptoms or obvious disability in
760-401: A study of forty-five children aged four to sixteen, two were found to be affected, aged 11 and 15. In a different 2008 study, the hearing of 41 people with OI was checked. The results showed that 88% of those over 20 years of age had some form of hearing loss, while only 38% of those under 20 did. Hearing loss is most common in type I OI; it is less common in types III and IV. Other parts of
836-404: A template for bone cells as skeletogenesis proceeds. Sp7/Osx null mouse embryos displayed a severe phenotype in which there were unaffected chondrocytes and cartilage but absolutely no formation of bone tissue. Ablation of Sp7 genes also led to decreased expression of various other osteocyte-specific markers such as: Sost, Dkk1 , Dmp1 , and Phe. The close relationship between Sp7/Osx and Runx2
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#1732801459766912-403: A ventilator to breathe. Type II is also known as the "lethal perinatal " form of OI, and is not compatible with survival into adulthood. Due to similarly severely deformed bones, sometimes infants with severe type III are wrongly initially classified as type II; once long-term survival is shown, they are considered as having type III instead. Collagen quantity is sufficient, but is not of
988-549: Is a protein that in humans is encoded by the SP7 gene . It is a member of the Sp family of zinc-finger transcription factors It is highly conserved among bone-forming vertebrate species It plays a major role, along with Runx2 and Dlx5 in driving the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes . Sp7 also plays a regulatory role by inhibiting chondrocyte differentiation maintaining
1064-483: Is a good indicator of susceptibility for osteoporosis in adults, the amount of information currently available from these studies does not allow for a direct correlation to be made between osteoporosis and Sp7. Abnormal expression of inflammatory cytokines such as TNF-α is present in osteoporosis can have detrimental effects on the expression of Sp7. Adiponectin is a protein hormone that has been shown to be upregulated in rheumatoid arthritis disease pathology, causing
1140-458: Is a partial cause of the abnormal degradation of bone seen in osteoporosis or rheumatoid arthritis The exact mechanisms of action for Sp7/Osterix are currently in contention and the full protein structure has yet to be solved. As a zinc-finger transcription factor, its relatively high homology with Sp1 seems to indicate that it might act in a similar fashion during gene regulatory processes. Previous studies done on Sp1 have shown that Sp1 utilizes
1216-494: Is associated with the Sp7 locus, adults and children with either low or high BMD were analyzed showing that several common variant SNPs within the 12q13 region were in an area of linkage disequilibrium. There are two main pathways which cause in the induction of Sp7/Osx gene expression. Msx2 induces Sp7 directly, whereas bone morphogenetic protein 2 (BMP2) induces it indirectly through either Dlx5 or Runx2 . Once Sp7 expression
1292-594: Is blue sclerae; in type III, infants commonly have blue sclerae that gradually turn white with age, but blue sclerae are not commonly seen in type IV, although they are seen in 10% of cases. OI type III causes osteopenic bones that fracture very easily, sometimes even in utero , often leading to hundreds of fractures during a lifetime; early scoliosis that progresses until puberty; dwarfism (a final adult height frequently less than 4 feet or 120 centimetres); loose joints; and possible respiratory problems due to low rib cage volume causing low lung volumes . Due to
1368-506: Is caused by mutations in Col1a1 or Col1a2 which are regulators of collagen growth. OI-causing mutations in these collagen genes are generally heritable in an autosomal-dominant fashion. However, there has been a recent case of a patient with recessive OI with a documented frameshift mutation in Sp7/Osx as the etiological origin of the disease. This patient displayed abnormal fracturing of
1444-471: Is decreased in mouse and human osteosarcoma cell lines when compared to endogenous osteoblasts and this decrease in expression correlates with metastatic potential. Transfection of the SP7 gene into a mouse osteosarcoma cell line to create higher levels of expression reduced overall malignancy in-vitro and reduced tumor incidence, tumor volume, and lung metastasis when the cells were injected into mice. Sp7 expression
1520-448: Is detrimental to the creation of ossified bone. Accelerated bone fracture healing was found when researchers implanted Sp7 overexpressing bone marrow stroma cells at a site of bone fracture. It was found that the mechanism by which Sp7 expression accelerated bone healing was through triggering new bone formation by inducing neighboring cells to express genes characteristic of bone progenitors. Along similar mechanistic lines as bone repair
1596-437: Is linked directly to OI type V. In the rare case of type XIX, first discovered in 2016, OI is inherited as an X-linked genetic disorder , with its detrimental effects resulting ultimately from a mutation in the gene MBTPS2 . Genetic research is ongoing, and it is uncertain when all the genetic causes of OI will be identified, as the number of genes that need to be tested to rule out the disorder continue to increase. In
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#17328014597661672-451: Is lost. OI is therefore a multi-scale phenomenon, where defects at the smallest levels of tissues (genetic, nano, micro) domino to affect the macro level of tissues . Diagnosis is typically based on medical imaging , including plain X-rays , and symptoms. In severe OI, signs on medical imaging include abnormalities in all extremities and in the spine. As X-rays are often insensitive to
1748-583: Is mostly defined in contrast to type III and type I, being the clinical classification for patients somewhere in the middle ground between the two. As such, type IV OI is often termed "variable" OI, with the severity of even those in the same family (so, with the same genetic mutation) differing. Prepubertal bone fracture rates are another way of clinically assessing type IV OI—those with it tend to have fracture rates of ≈1 per year, compared to ≈3 per year for severe OI (type III). As in type I, some further split type IV into types IV–A and IV–B, defined again by
1824-475: Is no cure, most cases of OI do not have a major effect on life expectancy, death during childhood from it is rare, and many adults with OI can achieve a significant degree of autonomy despite disability . Maintaining a healthy lifestyle by exercising , eating a balanced diet sufficient in vitamin D and calcium , and avoiding smoking can help prevent fractures. Genetic counseling may be sought by those with OI to prevent their children from inheriting
1900-608: Is of normal quality but is produced in insufficient quantities. Bones fracture more easily than in the general public, but not as easily as more severe types of OI; there might be scoliosis , albeit mild compared to OI types III and IV, with a lower Cobb angle ; the joints may be loose; blue sclerae may be apparent; hearing loss is likely to occur; and there might be a slight decrease in height. Because cases exist missing one or more of these symptoms, OI type I in some cases goes undetected into adulthood. Some further split type I into types I–A and I–B, defined as being distinguished by
1976-405: Is present, genetic sequencing of the most common problematic genes, COL1A1 , COL1A2 , and IFITM5 , may be done; if no mutation is found yet OI is still suspected, the other 10+ genes known to cause OI may be tested. Duplication and deletion testing is also suggested to parents who suspect their child has OI. The presence of frameshift mutations caused by duplications and deletions is generally
2052-525: Is significant genetic evidence for its role in diseases such as Osteogenesis imperfecta (OI). In humans Sp7 has been mapped to 12q13.13. It has 78% homology to another Sp family member, Sp1 , especially in the regions which code for the three Cys-2 His-2 type DNA-binding zinc fingers . Sp7 consists of three exons the first two of which are alternatively spliced, encoding a 431-residue isoform and an amino-terminus truncated 413-residue short protein isoform A GWAS study has found that bone mass density (BMD)
2128-519: Is suspected. There is no cure for osteogenesis imperfecta. Maintaining a healthy lifestyle by exercising and avoiding smoking can help prevent fractures. Treatment may include care of broken bones, pain medication, physical therapy , mobility aids such as braces or wheelchairs, and surgery. Judging the success or failure of treatment can be difficult in OI patients, as decreased bone fracture rates may just be coincidental. While these rates are often used in medical studies to judge treatment efficacy,
2204-440: Is the integration of dental implants into alveolar bone , since the insertion of these implants causes bone damage that must be healed before the implant is successfully integrated. Researchers have shown that when bone marrow stromal cells are exposed to artificially elevated levels of Sp7/Osx, mice with dental implants were shown to have better outcomes through the promotion of healthy bone regeneration. Overall Sp7 expression
2280-535: Is triggered, it then induces the expression of a slew of mature osteoblast genes such as Col1a1 , osteonectin , osteopontin and bone sialoprotein which are all necessary for productive osteoblasts during the creation of ossified bone. Negative regulation of this pathway comes in the form of p53 , microRNAs and the TNF inflammatory pathway. Disregulation of the TNF pathway blocking appropriate bone growth by osteoblasts
2356-588: The Endocrine Unit at the National Institute of Child Health in Karachi, Pakistan found an average of 5.8 fractures per year in untreated children. Fractures typically occur much less after puberty , but begin to increase again in women after menopause and in men between the ages of 60 and 80. Joint hypermobility is also a common sign of OI, thought to be because the affected genes are
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2432-595: The Wnt signaling pathway , the BRIL protein, et cetera. In type I the collagen's structure itself is normal, it is just its quantity that is low. Types II, III and IV are usually, but not always, related to a deficiency of type I collagen . One possible deficiency arises from an amino acid substitution of glycine to a bulkier amino acid, such as alanine , in the collagen protein's triple helix structure. The larger amino acid side-chains lead to steric effects that creates
2508-406: The lungs . As such, cardiovascular complications, among them aortic insufficiency , aortic aneurysm , and arterial dissections , are sometimes comorbid with OI, but not as frequently as they are comorbid with Marfan syndrome . Respiratory illnesses are a major cause of death in OI. The most obvious source of respiratory problems in OI is pulmonary insufficiency caused by problems in
2584-439: The skeleton as well as on the body's other organs —may be mild to severe. Symptoms found in various types of OI include whites of the eye (sclerae) that are blue instead, short stature , loose joints , hearing loss , breathing problems and problems with the teeth ( dentinogenesis imperfecta ). Potentially life-threatening complications , all of which become more common in more severe OI, include: tearing ( dissection ) of
2660-555: The GC box paradigm. Sp7 acts as a master regulator of bone formation during both embryonic development and during the homeostatic maintenance of bone in adulthood. In a developing organism, Sp7 serves as one of the most important regulatory shepherds for bone formation. The creation of ossified bone is preceded by the differentiation of mesenchymal stem cells into chondrocytes and the conversion of some of those chondrocytes into cartilage. Certain populations of that initial cartilage serves as
2736-459: The absence (IV–A) or presence (IV–B) of dentinogenesis imperfecta . As of 2020, fifteen types of OI are defined genetically: Given the rapid rate of type discovery, it is extremely likely that there are other genes associated with OI that have yet to be reported. Osteogenesis imperfecta is a group of genetic disorders, all of which cause bone fragility. OI has high genetic heterogeneity , that is, many different genetic mutations lead to
2812-462: The absence (I–A) or presence (I–B) of dentinogenesis imperfecta (opalescent teeth). People with type I generally have a normal lifespan. Collagen is fatally defective at its C-terminus . Most cases result in death shortly after birth, or within the first year of life, due to respiratory failure . Another common cause of death is intracranial bleeds from skull fractures present at, or sustained during or shortly after, birth. In many cases,
2888-443: The architecture of the thoracic wall . However, respiratory tract infections , such as pneumonia , are also more fatal among those with OI than the general population. Those with more severe ribcage deformities were found to have worse lung restriction in a small-scale 2012 study involving 22 Italian patients with OI types III and IV, plus 26 non-affected controls . OI—especially its severe form type III—also has effects on
2964-440: The balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage. Mutations of this gene have been associated with multiple dysfunctional bone phenotypes in vertebrates. During development, a mouse embryo model with Sp7 expression knocked out had no formation of bone tissue. Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density. In addition there
3040-411: The bones after relatively minor injuries and markedly delayed motor milestones, requiring assistance to stand at age 6 and was unable to walk at age 8 due to pronounced bowing of the arms and legs. This provides a direct link between the Sp7 gene and the OI disease phenotype. GWAS studies have shown associations between adult and juvenile bone mass density (BMD) and the Sp7 locus in humans. Though low BMD
3116-471: The cause of increased severity of disease. An important differential diagnosis of OI is child abuse , as both may present to a clinician with multiple fractures in various stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are present. This can become an issue in court; in the United States, several child abuse cases were resolved with
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3192-523: The collagen 1 proteins which causes the recessive form of the disorder. There are three significant types of OI that are a result of mutations in the collagen prolyl 3-hydroxylation complex (components CRTAP, P3H1, and CyPB). These components are responsible for the modification of collagen α1(l)Pro986. Mutations in other genes such as SP7 , SERPINF1 , TMEM38B and BMP1 can also lead to irregularly formed proteins and enzymes that result in other recessive types of osteogenesis imperfecta. Defects in
3268-472: The comparatively smaller bone density loss associated with type I OI, DEXA scans may be needed. An OI diagnosis can be confirmed through DNA or collagen protein analysis , but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue sclerae are sufficient for a diagnosis. A skin biopsy can be performed to determine the structure and quantity of type I collagen. While DNA testing can confirm
3344-562: The diagnosis, it cannot absolutely exclude it because not all mutations causing OI are yet known and/or tested for. OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be visible. Relative to control, OI cortical bone shows increased porosity, canal diameter, and connectivity in micro-computed tomography. OI can also be detected before birth by using an in vitro genetic testing technique such as amniocentresis . In order to determine whether osteogenesis imperfecta
3420-398: The disorder (its type). Type I (the least severe) is the most common, with other types comprising a minority of cases. Moderate-to-severe OI primarily affects mobility; if rodding surgery is performed during childhood, some of those with more severe types of OI may gain the ability to walk. The condition has been described since ancient history. The Latinate term osteogenesis imperfecta
3496-421: The disorder from them. Treatment may include acute care of broken bones, pain medication , physical therapy , mobility aids such as leg braces and wheelchairs , vitamin D supplementation , and, especially in childhood, rodding surgery . Rodding is an implantation of metal intramedullary rods along the long bones (such as the femur ) in an attempt to strengthen them. Medical research also supports
3572-423: The dominant form of OI. These factors include: intracellular stress; abnormal tissue mineralization; abnormal cell to cell interactions; abnormal cell- matrix interactions; a compromised cell matrix structure; and, abnormal interaction between non-collagenous proteins and collagen. Previous research led to the belief that OI was an autosomal dominant disorder with few other variations in genomes. However, with
3648-615: The fracture seems trivial ( microfracture ), as people with OI are at greater risk of nonunion. Bone infections secondary to fractures are treated as and when they occur with the appropriate antibiotics and antiseptics , as in the general population. In 1998, an initial observational trial demonstrated the effectiveness of intravenous pamidronate , a bisphosphonate which had previously been used in adults to treat osteoporosis . In severe OI, this trial showed that pamidronate reduced bone pain, prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced
3724-436: The fracture, as in moderate or severe types of OI, using heavy casts , such as hip spica casts, can cause fractures at the bones at the boundaries of the cast, as well as generalized osteopenia . The lightweight cast or splint is then replaced with a removable orthosis after a few weeks and once evidence of union is seen on X-ray. In order to prevent a nonunion or malunion , all fractures should be immobilized, even if
3800-661: The gastrointestinal system. It was found to be associated with recurrent abdominal pain and chronic constipation in two studies on patients affected by OI. Chronic constipation is especially common, and is thought to be aggravated by an asymmetric pelvis ( acetabular protrusion ). Especially in childhood, OI-associated constipation may cause a feeling of fullness and associated food refusal, leading to malnutrition . There are two typing systems for OI in modern use. The first, created by David Sillence in 1979, classifies patients into four types, or syndromes , according to their clinical presentation , without taking into account
3876-530: The genetic cause of their disease. The second system expands on the Sillence model, but assigns new numbered types genetically as they are found. Therefore, people with OI can be described as having both a clinical type and a genetic type, which may or may not be equivalent. Type I is the most common, and 90% of cases result from mutations to either COL1A1 or COL1A2 . Symptoms vary widely between types, as well as vary from person to person, even in
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#17328014597663952-411: The inner ear may also be affected by OI. causing balance issues; however, only small studies have found links between vertigo and OI. OI may worsen the outcome of medical treatments which correct hearing loss. Besides OI's association with sensorineural hearing loss, OI is associated with a number of neurological abnormalities, usually involving the central nervous system , due to deformities in
4028-449: The least severe; type IV, moderately severe; type III, severe and progressively deforming; and type II, perinatally lethal. As of September 2021 , 19 different genes are known to cause the 21 documented genetically defined types of OI, many of which are extremely rare and have only been documented in a few individuals. Diagnosis is often based on symptoms and may be confirmed by collagen biopsy or DNA sequencing . Although there
4104-551: The lowering of the cost of DNA sequencing in the wake of 2003's Human Genome Project , autosomal recessive forms of the disorder have been identified. Recessive forms of OI relate heavily to defects in the collagen chaperones responsible for production of procollagen and the assembly of the related proteins. Examples of collagen chaperones that are defective in patients with recessive forms of OI include chaperone HSP47 ( Cole-Carpenter syndrome ) and FKBP65 . Mutations in these chaperones result in an improper folding pattern in
4180-600: The major arteries , such as the aorta ; pulmonary valve insufficiency secondary to distortion of the ribcage ; and basilar invagination . The underlying mechanism is usually a problem with connective tissue due to a lack of, or poorly formed, type I collagen . In more than 90% of cases, OI occurs due to mutations in the COL1A1 or COL1A2 genes. These mutations may be hereditary in an autosomal dominant manner but may also occur spontaneously ( de novo ). There are four clinically defined types: type I,
4256-564: The newborn already has multiple broken bones at the time of birth. Type II infants also exhibit severe respiratory problems, and have severely deformed bones. Sixty percent of infants die less than 24 hours after being born, and survival after the first year is extremely unlikely and normally requires mechanical ventilation . In the rare cases of infants who survive their first year of life, severe developmental and motor delays are seen; neither of two infants studied in 2019, both aged around two years, had achieved head control , and both required
4332-466: The parent—the parent's different cells have two (or more) sets of slightly different DNA. It has been clinically observed that ≈5–10% of cases of OI types II and III are attributable to genetic mosaicism. People with OI are either born with defective connective tissue , born without the ability to make it in sufficient quantities, or, in the rarest genetic types, born with deficiencies in other aspects of bone formation such as chaperone proteins ,
4408-407: The phenotype observed was related to an abundance of initiation sites for bone proliferation creating many pseudo- sutures . The most direct example of the role of Sp7 in human disease has been in recessive osteogenesis imperfecta (OI), which is a type-I collagen related disease that causes a heterogeneous set of bone-related symptoms which can range from mild to very severe. Generally this disease
4484-424: The primary disease process of OI happens in the bones, the most common types of OI —those caused by type I collagen gene mutations—affect virtually all of the human body's organs in some way. Type I collagen is present throughout the circulatory and respiratory systems : from the ventricles of the heart itself, to the heart valves , to the vasculature , it is an integral part of the connective tissue of
4560-466: The progenitor cells take the pathway into becoming chondrocytes and eventually cartilage rather than creating ossified bone. Outside of the context of development, in adult mice ablation of Sp7 led to a lack of new bone formation, highly irregular cartilage accumulation beneath the growth plate and defects in osteocyte maturation and functionality. Other studies observed that a conditional knockout of Sp7 in adult mice osteoblasts resulted in osteopenia in
4636-488: The protein known as homeobox transcription factor Dlx5 . This is plausible because Dlx5 has much higher affinity to AT-rich gene regulatory regions than Sp7 has been shown to have to the GC box thus providing an alternate methodology through which regulation can occur. Mass spectrometry and proteomics methods have shown that Sp7 also interacts with RNA helicase A and is possibly negatively regulated by RIOX1 both of which provide evidence for regulatory mechanisms outside of
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#17328014597664712-485: The proteins pigment epithelium-derived factor (PEDF) and bone-restricted interferon-induced transmembrane protein (BRIL) are the causes of type V and VI osteogenesis imperfecta. Defects in these proteins lead to defective bone mineralization which causes the characteristic brittle bones of osteogenesis imperfecta. A single point mutation in the 5′ untranslated region (5′ UTR) of the IFITM5 gene, which encodes BRIL,
4788-504: The release of inflammatory cytokines and enhancing the breakdown of the bone matrix. In primary human cell cultures Sp7 was shown to be inhibited by adiponectin thus contributing downregulation of the creation of ossified bone. This data is further backed up by another study in which inflammatory cytokines such as TNF-α and IL-1β were shown to downregulate gene expression of Sp7 in mouse primary mesenchymal stem cells in culture. These studies seem to indicate that an inflammatory environment
4864-447: The rest of the skeleton largely unaffected. Instead of normal suture patterning along the developing skull, the affected organisms displayed a mosaic of sites where bone formation was being initiated but not completed. This caused the appearance of many small irregular bones instead of the normal smooth frontal and parietal bones. These phenotypic shifts corresponded to an overproliferation of Runx2+ osteoblast progenitors indicating that
4940-453: The same as those that cause some types of Ehlers–Danlos syndrome . By the age of 50, about 50% of adults with OI experience significant hearing loss , much earlier as compared to the general population. Hearing loss in OI may or may not be associated with visible deformities of the ossicles and inner ear . Hearing loss frequently begins during the second, third, and fourth decades of life, and may be conductive , sensorineural , or
5016-505: The same family. As of 2021, 21 types of OI have been defined: Sillence's four types have both a clinical and a genetic meaning; the descriptions below are clinical and can be applied to several genetic types of OI. When used to refer to a genetic as well as a clinical type, it indicates that the clinical symptoms are indeed caused by mutations in the COL1A1 or COL1A2 genes which are inherited in an autosomal dominant fashion. Collagen
5092-415: The same or similar sets of observable symptoms ( phenotypes ). The main causes for developing the disorder are a result of mutations in the COL1A1 and/or COL1A2 genes which are jointly responsible for the production of collagen type I . Approximately 90% of people with OI are heterozygous for mutations in either the COL1A1 or COL1A2 genes. There are several biological factors that are results of
5168-507: The severity of the issues with the bones, neurological and seizure disorders are more likely to develop in type III. Basilar invagination , which puts pressure on the brainstem , may cause or contribute to early death; surgical treatment of it is more complex in OI cases. Collagen quantity is sufficient, but is not of a high enough quality. Type IV is for cases of variable severity, which do not fit into either types III or I. While one of Sillence's required characteristics for type IV
5244-570: The skeletal structures surrounding it. Neurological complications, especially basilar invagination , may adversely affect life expectancy. In OI, this is most often due to upwards migration of the dens , a feature of the C2 vertebra . Neurosurgery may be needed to correct severe abnormalities when they risk the patient's life or cause either great suffering or intolerable neurological deficits . As its biological causes have been more precisely determined, it has become more widely recognized that while
5320-405: The use of medications of the bisphosphonate class, such as pamidronate , to increase bone density . Bisphosphonates are especially effective in children; however, it is unclear if they either increase quality of life or decrease the rate of fracture incidence. OI affects only about one in 15,000 to 20,000 people, making it a rare genetic disease . Outcomes depend on the genetic cause of
5396-401: The vertebrae of the animals, issues with bone turnover and more porosity in cortical outer surface of the long bones of the body. Observation of an opposite effect, overproliferation of Sp7+ osteoblasts, further supports the important regulatory effects of Sp7 in vertebrates. A mutation in the zebrafish homologue of Sp7 caused severe craniofacial irregularities in maturing organisms while leaving
5472-530: The zinc-finger DNA binding domains in its structure to bind directly to a GC-rich region of the genome known as the GC box . creating downstream regulatory effects. There are a number of studies which support this mechanism as also applicable for Sp7, however other researchers were unable to replicate the GC box binding seen in Sp1 when looking at Sp7. Another proposed mechanism of action is indirect gene regulation through
5548-586: Was also demonstrated through this particular experiment because the Sp7 knockout bone phenotype greatly resembled that of the Runx2 knockout, and further experiments proved that Sp7 is downstream of and very closely associated with Runx2. The important conclusion of this particular series of experiments was the clear regulatory role of Sp7 in the decision process made by mesenchymal stem cells to progress from their original highly Sox9 positive osteoprogenitors into either bone or cartilage. Without sustained Sp7 expression
5624-487: Was also found to decrease bone destruction by the sarcoma likely through supplementing the normal regulatory pathways controlling osteoblasts and osteocytes. Osteogenesis imperfecta Osteogenesis imperfecta ( IPA : / ˌ ɒ s t i oʊ ˈ dʒ ɛ n ə s ɪ s ˌ ɪ m p ɜːr ˈ f ɛ k t ə / ; OI ), colloquially known as brittle bone disease , is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on
5700-412: Was coined by Dutch anatomist Willem Vrolik in 1849; translated literally, it means "imperfect bone formation". The main symptom of osteogenesis imperfecta is fragile, low mineral density bones ; all types of OI have some bone involvement. In moderate and especially severe OI, the long bones may be bowed , sometimes extremely so. The weakness of the bones causes them to fracture easily—a study at
5776-413: Was having normal sclerae, modern classification allows even those with blue sclerae to fit the criteria for type IV if they meet the other clinical requirements of the type. In type IV, bone deformity can be mild to severe, bones fracture easily (especially before puberty), dwarfism is common, vertebral collapse and scoliosis are evident, and hearing loss is possible, although uncommon. Type IV OI
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