Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in theCOL1A1 andCOL1A2 genes of type I collagen

Byers, Peter H.; Duvic, Madeleine; Atkinson, Mary; Robinow, Meinhard; Smith, Lynne T.; Krane, Stephen M.; Greally, Marie T.; Ludman, Mark D.; Matalon, Reuben; Pauker, Susan P.; Quanbeck, Deborah S.; Schwarze, Ulrike

doi:10.1002/(sici)1096-8628(19971003)72:1<94::aid-ajmg20>3.0.co;2-o

Cited by 126 publications

(84 citation statements)

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“…Similar mutations in the COL1A2 gene are less likely to be lethal unless the affected sequences are located near the carboxyl-terminal end of the triple helix (Kiuvaniemi et al 1997) or when the other COL1A2 allele is a null allele (Tromp and Prockop 1988). In both genes, skipping of exon 6 produces an Ehlers-Danlos syndrome type VII phenotype in which the amino-terminal propeptide of the respective chain is retained because the procollagen N-proteinase cleavage site encoded in exon 6 is deleted (Byers et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII

Raff¹,

Craigen²,

Smith³

et al. 2000

Human Genetics

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Type I collagen is the most abundant structural protein in the mammalian body. It exists as a heterotrimer of two subunits in the form [alpha1(I)]2alpha2(I). Pathogenic mutations in COL1A1 and COL1A2, the genes that encode the two subunits, cause a range of phenotypes including mild to lethal forms of osteogenesis imperfecta and a restricted set of Ehlers-Danlos syndrome phenotypes. Lethal mutations usually result from missense mutations that disrupt the normal triple helical structure of the molecule. Multi-exon duplication or deletion in type I collagen genes has rarely been observed and has generally resulted in a lethal or severe phenotype. We report a partial duplication in the COLIA2 gene that causes a relatively mild phenotype, despite the addition of 477 amino acids to the triple helical domain of the proalpha2(I) chain. The abnormal molecule is synthesized and secreted by cultured dermal fibroblasts in a normal fashion. Electron microscopy of dermal tissue reveals small but otherwise near normal collagen fibrils. The gene duplication occurred by mitotic sister chromatid exchange in the mother who is mosaic for the duplication allele. Examination of the abnormal sequence suggests a means by which the duplicated molecule could be processed and properly incorporated into mature collagen fibrils.

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Section: Discussionmentioning

confidence: 99%

Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII

Raff¹,

Craigen²,

Smith³

et al. 2000

Human Genetics

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“…Furthermore, the N propeptide in the extracellular matrix binds to specific cytokines (for example, transforming growth factor β1 (TGFβ1) and BMP2), which are crucial for bone development 42 . Mutations that remove the N terminal cleavage site residues due to exon skipping 43 cause Ehlers-Danlos syndrome, and not osteogenesis imperfecta…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

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582

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| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

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“…The pN-SQT-1 molecules dominantly disrupt the normal cuticle structure. Mutations that alter the procollagen N-proteinase processing site of human type I collagen cause autosomal dominant Ehlers-Danlos syndromes type VIIA and VIIB (26). These patients have joint hypermobility and subluxations, hip dislocations, scoliosis, and increased bone fractures.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular weight standards (Roche Molecular Biochemicals) used were: ␣ 2 -macroglobulin (170,000 Da), ␤-galactosidase (116,400), fructose-6-phosphate kinase (85,000), glutamate dehydrogenase (55,600), aldolase (39,200), and triose-phosphate isomerase (26,600). Gels were stained with 0.5% Coomassie Brilliant Blue R-250 (Sigma) in 40% methanol and 10% acetic acid for 30 min, and destained in 10% methanol, 10% acetic acid.…”

mentioning

confidence: 99%

Proteolytic Processing of Caenorhabditis elegansSQT-1 Cuticle Collagen Is Inhibited in Right Roller Mutants whereas Cross-linking Is Inhibited in Left Roller Mutants

Yang¹,

Kramer

1999

Journal of Biological Chemistry

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The sqt-1 gene encodes a C. elegans cuticle collagen that when defective can cause dramatic alterations of organismal morphology. Specific antisera were used to examine the assembly of wild-type and mutant SQT-1 in the cuticle. Wild-type SQT-1 chains associate into dimer, tetramer, and higher oligomers that are cross-linked by non-reducible, presumably tyrosine-derived, covalent bonds. The SQT-1 pattern differs from the bulk of cuticle collagens which are found in trimer and larger forms. sqt-1 mutations that cause left-handed helical twisting of animals remove a conserved carboxyl-domain cysteine and inhibit formation of these non-reducible bonds. SQT-1 monomers accumulate and novel trimersized products form. A conserved tyrosine immediately adjacent to the affected cysteine suggests that disulfide bond formation is required for this tyrosine to form a cross-link. sqt-1 mutations that cause right-handed helical twisting affect conserved arginines in a predicted cleavage site for a subtilisin-like protease. These mutant SQT-1 molecules retain residues on the amino side of the predicted cleavage site and are larger than wild-type by the amount expected if cleavage failed to occur. The conservation of this site in all nematode cuticle collagens indicates that they are all synthesized as procollagens that are processed by subtilisin-like proteases.The cuticle (exoskeleton) of the nematode Caenorhabditis elegans is a complex, multilayered extracellular structure composed primarily of collagens encoded by a family of approximately 150 genes (1, 2). The cuticle collagens all have similar domain structures (3) (Fig. 1). The central Gly-X-Y repeat domain contains two to four interruptions of non-Gly-X-Y sequence and is flanked by three cysteines on the amino side and two cysteines on the carboxyl side. The precise positions of these cysteine residues differs in different subfamilies of the cuticle collagen genes. The amino-terminal domain contains four short conserved stretches of amino acids that are referred to as homology blocks A-D. The carboxyl-domain is generally short and contains cysteine and tyrosine residues, the positions of which are generally conserved within but not between subfamilies.With a few exceptions, the cuticle collagen genes are predicted to encode polypeptides of about 30 kDa. However, reductive extraction of cuticles results in collagen molecules that migrate with apparent molecular masses from 90 to over 200 kDa (4,5). The unexpectedly low mobility of the cuticle collagens is due to cross-linking between chains by di-, tri-, and/or isotri-tyrosine residues (6, 7). These cross-links are non-reducible and result in the formation of multimers of the collagen chains.Mutations in C. elegans cuticle collagens can cause a variety of gross morphological defects, including dumpy (Dpy, 1 short and fat), long (Lon, long and thin), roller (Rol, helically twisted), and abnormal tail structure (Tal, defective tail structure) (1, 2). Roller mutants can be twisted in either a left-handed (LRol) or right-hande...

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Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in theCOL1A1 andCOL1A2 genes of type I collagen

Cited by 126 publications

References 41 publications

Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII

Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII

Osteogenesis imperfecta

Proteolytic Processing of Caenorhabditis elegansSQT-1 Cuticle Collagen Is Inhibited in Right Roller Mutants whereas Cross-linking Is Inhibited in Left Roller Mutants

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