More than 2000 different pathogenic variants affecting the synthesis or structure of type I collagen have been found in individuals with OI. The clinical heterogeneity of this disease reflects even greater heterogeneity at the molecular level. For the type I collagen genes, the variants fall into two general classes, those that reduce the amount of type I procollagen made and those that alter the structure of the molecules assembled.

Type I: Diminished Collagen Production. Most individuals with OI type I have variants that result in production by cells of approximately half the normal amount of type I procollagen. Most of these variants result in premature termination codons in one COL1A1 allele that render the mRNA from that allele untranslatable. Because type I procollagen molecules must have two proα1(I) chains to assemble into a triple helix, loss of half the mRNA leads to production of half the normal quantity of type I procollagen molecules, although these molecules are normal. Missense variants can also give rise to this milder form of OI when the amino acid change is located in the amino terminus. This is because amino terminal substitutions tend to be less disruptive of collagen chain assembly, which can still initiate as usual at the carboxy terminus.

Types II, III, and IV: Structurally Defective Collagens. The type II, III, and IV phenotypes of OI usually result from variants that produce structurally abnormal proα1(I) or proα2(I) chains (see Fig. 13.20 and Table 13.4). Most of these patients have substitutions in the triple helix that replace a glycine with a bulkier residue that disrupts formation of the triple helix. The specific collagen affected, the location of the substitution, and the nature of the substituting residue are all important phenotypic determinants, but some generalizations about the phenotype likely to result from a specific substitution are nevertheless possible. Thus substitutions in the proα1(I) chain are more prevalent in patients with OI types III and IV and are more often lethal. In either chain, replacement of glycine (a neutral residue) with a charged residue (aspartic acid, glutamic acid, arginine) or large residue (tryptophan) is usually very disruptive and often associated with a severe (type II) phenotype. Sometimes, a specific substitution is associated with more than one phenotype, an outcome that is likely to reflect the influence of powerful modifier genes.

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مواضيع ذات صلة

The Genetics of Osteogenesis Imperfecta

Prenatal Diagnosis of Hereditary Genetic Diseases

Prenatal Diagnosis of Non-hereditary Genetic Diseases

Clinical Applications of Gene Testing in Muscular Dystrophy

The Genetics of Duchenne Muscular Dystrophy and Becker Muscular Dystrophy

Pathogenic Variants of an Enzyme Inhibitor: α1-Antitrypsin Deficiency

Lysosomal Storage Diseases: A Unique Class of Enzymopathies

Aminoacidopathies

Diseases due to pathogenic variants in different classes of proteins

Renal cysts and diabetes (HNF1B MODY)

Maternally inherited diabetes and deafness

Genetic testing in neonatal diabetes