FOR several decades it has been apparent that many diseases directly or indirectly involve collagen, the tough fibrous material that is the most abundant protein in the body and the major constitue...

Heritable Diseases of Collagen

The collagens represent an interesting example of a structurally related but genetically distinct family of proteins1. Type I, the most abundant of the vertebrate collagens, comprises two proα1(I) chains and one proα2(I) chain, each containing terminal propeptides and a central domain of 338 (Gly, X, Y) repeats. The structure of the chicken proα2(I) gene shows an intriguing relationship between exon organization and the arrangement of (Gly, X, Y) repeats (see ref. 2 for review). This has led to the suggestion3 that the collagens evolved from a common ancestral unit of 54 base pairs (bp). Here we present the structure of the entire human proα1(I) gene and compare this with the chicken proα2(I). The exon arrangement of the two genes is remarkably similar, although the human proα1(I) is more compact because of the shorter length of its introns. The data strongly support the notion that the type I genes have evolved from an ancestral multi-exon unit, and that once the gene was translated, a strong evolutionary pressure caused it to maintain this elaborate structure.

Human proα1(I) collagen gene structure reveals evolutionary conservation of a pattern of introns and exons

Ascorbic Acid Specifically Increases Type I and Type III Procollagen Messenger RNA Levels in Human Skin Fibroblasts

cDNA clones coding for the pro-alpha1(IV) chain of human type IV procollagen reveal an unusual homology of amino acid sequences in two halves of the carboxyl-terminal domain.

Cloned probes specific for unique genes have proven to be powerful tools in defining the nature of genetic diseases such as the thalassaemias and growth hormone deficiencies. A similar approach should be useful in defining heritable diseases of type I collagen, the heterotrimer of two alpha 1(I) chains and one alpha 2(I) chain, which is the most abundant member of the collagen family of proteins. Recently, cloned cDNAs and genomic DNAs for the two polypeptide chains of the type I collagen have become available and have been used to elucidate the chromosomal location of the corresponding genes. Here, we have used several of these cloned DNAs to demonstrate the presence of an internal deletion of about 0.5 kilobases (kb) in one allele for the pro alpha 1(I) chain in a patient with osteogenesis imperfecta (OI), a group of heritable disorders which are characterized by brittle bones but which are highly heterogeneous both phenotypically and biochemically.

Internal deletion in a collagen gene in a perinatal lethal form of osteogenesis imperfecta.

A recombinant plasmid containing sequences complementary to human pro-alpha l(I) collagen mRNA was used for the chromosomal assignment of the pro-alpha l(I) collagen gene. Restriction endonuclease analysis of DNA from mouse-human and Chinese hamster-human somatic cell hybrids revealed cosegregation with human chromosome 17. Hybrids containing derivative chromosomes with a t(2;17)(q14;q21) translocation showed cosegregation of the pro-alpha l(I) gene with the segment 17q21 leads to qter. In situ hybridization on human metaphasic chromosomes confirmed this conclusion.

https://www.pnas.org/content/pnas/79/21/6627.full.pdf

A. Boué

Papers

Human type I procollagen genes are located on different chromosomes.

Section 2: Chromosome disease

Workshop on collaborative studies in prenatal diagnosis of chromosome disease.