Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce ehlers-danlos syndrome type I

Abstract

Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder that severely impairs the structure and function of the skin, joints, eyes and blood vessels. We have identified mutations of the COL5A2 gene, which encodes the alpha2(V) chain of type V collagen, in two unrelated patients with the severe type I form of EDS. The first proband was heterozygous for a 7 bp deletion that resulted in skipping of exon 27 while the second proband was heterozygous for a single nucleotide substitution that resulted in skipping of exon 28. Cultured dermal fibroblasts from both probands produced about equal amounts of the normal and mutant alpha2(V) mRNAs and protein chains. The dermis from the first proband contained a sparse collagen fibrillar network with great variability in collagen fibril sizes and shapes. The dermal collagens were also abnormally soluble. Bone cells from the first proband also produced about equal amounts of the normal and mutant alpha2(V) mRNAs. However, the collagen fibrillar architecture and collagen solubility of the bone matrix were normal. Our findings show that heterozygous mutations of the COL5A2 gene can produce the EDS type I phenotype. They also suggest that type V collagen plays a more important role in collagen fibrillogenesis of dermis than that of bone.

Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type

“…These structural mutations are most commonly splice site mutations that result in exon skipping and a few point mutations that result in the substitution for glycine in the triple-helical region of the collagen molecule. 49,[55][56][57][58][59][60][61] In contrast to other disorders characterized by mutations in the fibrillar collagen genes, remarkably few mutations have been found that result from the substitution of a glycine by a bulkier amino acid.…”

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

“…Accordingly, mutations in COL5A2 (MIM *120190), which encodes the a2 chain of type V collagen, lead to the classical type of EDS (EDS I/II, MIM #130000/#130010), the major diagnostic criteria of which include skin hyperextensibility, widened atrophic scars, and joint hypermobility but no AD. 14,22 The SLC40A1 gene (SLC11A3, MIM *604653) encodes ferroportin and has been associated with hemochromatosis type 4 (HFE4, MIM #606069), a disorder of iron homeostasis. 23,24 MSTN (MIM +601788) encodes the muscle growth inhibitor myostatin and has been found to be mutated in incomplete autosomal dominant muscle hypertrophy (MIM +601788).…”

Pachydermodactilia in a patient with non-differentiated connective tissue dysplasia

“…Следствием этого является расстройство гомеостаза на тканевом, органном и организменном уровнях, что сопровождается раз-личными морфофункциональными нарушениями висцеральных и локомоторных систем с прогреди-ентным течением [12,13].…”

“…Морфологические изме-нения в тканях и органах неспецифичны и проявля-ются сходным образом при различных дисплазиях с разной степенью выраженности [13]. Характер по-ражения органов обусловлен их собственными па-ренхиматозно-стромальными взаимоотношениями [12].…”