As just discussed, most of the variants in type I colla gen genes that cause OI act in a dominant manner. This group of disorders illustrates the genetic complexities that result when variants alter structural proteins, particularly those composed of multiple different subunits, or alter proteins that are involved in the folding and transport of collagens to their place of action.

The relatively mild phenotype and dominant inheritance of OI type I are consistent with the fact that although only half the normal number of molecules is made, they are of normal quality (see Fig. 1). The more severe consequences of producing structurally defective proα1(I) chains from one allele (compared with producing no chains) partly reflect the stoichiometry of type I collagen, which contains two proα1(I) chains and one proα2(I) chain (see Fig. 1). Accordingly, if half the proα1(I) chains are abnormal, three of four type I molecules have at least one abnormal chain; in contrast, if half the proα2(I) chains are defective, only one in two molecules is affected. Variants such as the proα1(I) missense allele (proα1^M) shown in Fig. 1 are thus dominant negative alleles because they impair the contribution of both the normal proα1(I) chains and the normal proα2(I) chains. In other words, the effect of the mutant allele is amplified because of the trimeric nature of the collagen molecule. Consequently, in dominantly inherited diseases such as OI, it is actually better to have a variant that generates no gene product than one that produces an abnormal gene product. The bio chemical mechanism in OI by which the dominant negative effect of dominant negative alleles of the COL1A1 genes is exerted is one of the best understood in all of human genetics.

Fig2. The pathogenesis of the major classes of type I procollagen mutants. (Column 1) The types of procollagen chains available for assembly into a triple helix. Although there are two α1 and two α2 collagen genes/genome, as implied in the left column, twice as many α1 collagen molecules are produced, compared to α2 collagen molecules, as shown in the central column. (Column 2) The effect of type I procollagen stoichiometry on the ratio of normal to defective collagen molecules formed in mutants with proα1 chain versus proα2 chain variants. The small vertical bars on each procollagen chain indicate posttranslational modifications (see text). (Column 3) The effect of variants on the biochemical processing of collagen. OI, Osteogenesis imperfecta; Proα1M, a proα1 chain with a missense variant; Proα2M, a proα2 chain with a missense variant; Proα10, a proα1 chain null allele.

Although variants that produce structurally abnormal proα2(I) chains reduce the number of normal type I collagen molecules by half, this reduction is nevertheless sufficient, in the case of some variants, to cause the severe perinatal lethal phenotype (see Table 1). Most infants with OI type II, the perinatal lethal form, have a de novo dominant mutation, and consequently there is a very low likelihood of recurrence in the family. In occasional families, however, more than one sibling is affected with OI type II. Such recurrences are usually due to parental germline or gonadal mosaicism.

Table1. Summary of the Genetic, Biochemical, and Molecular Features of the Types of Osteogenesis Imperfecta Due to Variants in Type 1 Collagen Genes

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مواضيع ذات صلة

Molecular Abnormalities of Collagen in 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