Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development

Abstract

Type III collagen is a fibrillar forming collagen comprising three ␣1(III) chains and is expressed in early embryos and throughout embryogenesis. In the adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and skin. Mutations in the COL3A1 gene have been implicated as a cause of type IV Ehlers-Danlos syndrome, a disease leading to aortic rupture in early adult life. To directly study the role of Col3a1 in development and disease, we have inactivated the Col3a1 gene in embryonic stem cells by homologous recombination. The mutated allele was transmitted through the mouse germ line and homozygous mutant animals were derived from heterozygous intercrosses. About 10% of the homozygous mutant animals survived to adulthood but have a much shorter life span compared with wild-type mice. The major cause of death of mutant mice was rupture of the major blood vessels, similar to patients with type IV Ehlers-Danlos syndrome. Ultrastructural analysis of tissues from mutant mice revealed that type III collagen is essential for normal collagen I fibrillogenesis in the cardiovascular system and other organs.

Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

“…In animal models, mice homozygous for an inactivated allele of Col3a1 showed a phenotype closely resembling EDS IV, whereas heterozygous mice were phenotypically normal. 31 Late-onset signs in heterozygous mice, however, could not be excluded, because these mice had a limited follow-up period (cf. there are functional changes in bladder tissue of 8-week-old mice heterozygous for a Col3a1 null allele).…”

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

“…In connective tissues, including blood vessels and skin, collagen type III colocalizes with collagen type I within the same fibril, presumably to regulate the size of collagen type I fibrils (Fleischmajer et al, 1988(Fleischmajer et al, , 1990. In Col3a1Ϫ/Ϫ mutant mice, electron microscopy detected collagen fibrils irregular in size in the skin and the adventitia of the aorta, indicating the necessity for collagen type III for normal collagen fibrillogenesis (Liu et al, 1997). Ultrastructural analysis of mice harboring a targeted disruption of the decorin gene revealed abnormal collagen morphology in decorin-deficient tendon, with coarser fibrils and irregularities in size and shape when compared with wild-type tissue (Danielson et al, 1997).…”

“…Collagen type III is a member of the fibrillar collagen family and the second most abundant collagen molecule in tendon. Studies in skin, tendon, and other tissues indicate a role for collagen type III in regulating fibrillogenesis of collagen type I (Fleischmajer et al, 1988(Fleischmajer et al, , 1990Ros et al, 1995;Liu et al, 1997;Birk and Mayne, 1997). Decorin is a small chondroitin-dermatan sulfate proteoglycan consisting of a core protein and a single glycosaminoglycan chain, and is the most abundant proteoglycan in mature tendon (Goh et al, 2003).…”

Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome

“…uk/genetics/collagen/) 5 match with this model. Although biases related to the screening methods for mutation detection are possible, this mutation spectrum, the analogy with the COL1A1 and COL1A2 mutations spectrum observed in osteogenesis imperfecta (MIM#120150 and 120160, http://www.ncbi.nlm.nih.gov/Omim/), and the findings from a mouse knockout model for COL3A1 6 have long suggested that COL3A1 null alleles could confer attenuated phenotypes. However, in 2001, the study by Schwarze et al 7 questioned these genotype -phenotype correlations.…”