Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy

Abstract

Members of the type IV collagen family are essential components of all basement membranes (BMs) and define structural stability as well as tissue-specific functions. The major isoform, alpha1.alpha1.alpha2(IV), contributes to the formation of many BMs and its deficiency causes embryonic lethality in mouse. We have identified an allelic series of three ENU induced dominant mouse mutants with missense mutations in the gene Col4a1 encoding the alpha1(IV) subunit chain. Two severe alleles (Bru and Svc) have mutations affecting the conserved glycine residues in the Gly-Xaa-Yaa collagen repeat. Bru heterozygous mice display defects similar to Axenfeld-Rieger anomaly, including iris defects, corneal opacity, vacuolar cataracts, significant iris/corneal adhesions, buphthalmos and optic nerve cupping, a sign indicative of glaucoma. Kidneys of Bru mice have peripheral glomerulopathy characterized by hypertrophy and hyperplasia of the parietal epithelium of Bowman's capsule. A milder allele (Raw) contains a mutation in the Yaa residue of the collagen repeat and was identified by a silvery appearance of the retinal arterioles. All phenotypes are associated with BM defects that affect the eye, kidney and other tissues. This allelic series shows that mutations affecting the collagen domain cause dominant negative effects on the expression and function of the major collagen IV isoform alpha1(IV), and pathological effects vary with the individual mutations.

Basement membranes and human disease

“…Mutations affecting the Y residue of the G-X-Y repeat or residues in the NC1 domain result in milder phenotypes than mutations affecting glycine residues (Favor et al 2007;Van Agtmael et al 2005). This difference was also observed at the BM level suggesting BM defects underlie the phenotypes (Van Agtmael et al 2005). In this case the mutation may result in focal absence of α1.α1.α2(IV) and/or affect interactions with collagen type IV receptors such as integrins and DDR1, or other BM components.…”

“…In mice, Col4a1 missense mutations caused a mild glomerulopathy with extensive BM defects in Bowman's capsule (Fig. 5) (Van Agtmael et al 2005), mild BM abnormalities in the GBM, and proteinuria (Favor et al 2007;Gould et al 2006). Some of these phenotypes were also observed in HANAC syndrome (hereditary angiopathy with nephropathy, aneurysm and cramps) caused by COL4A1 missense mutations.…”

“…Other COL4A1 mutations have been described in families with vascular and eye disease (Breedveld et al 2006;de Vries et al 2009;Gould et al 2005;Gould et al 2006;Shah et al 2009;Vahedi et al 2007b;van der Knaap et al 2006) (see below), but it is not known whether these patients have renal phenotypes. Analysis of patients and ENU mouse models with COL4A1 mutations has revealed that the mutations result in a spectrum of phenotypes determined by the individual mutation (Van Agtmael et al 2005), its location within the gene and genetic and environmental modifiers (Gould et al 2007;Gould et al 2006). Mutations affecting the Y residue of the G-X-Y repeat or residues in the NC1 domain result in milder phenotypes than mutations affecting glycine residues (Favor et al 2007;Van Agtmael et al 2005).…”

“…Analysis of patients and ENU mouse models with COL4A1 mutations has revealed that the mutations result in a spectrum of phenotypes determined by the individual mutation (Van Agtmael et al 2005), its location within the gene and genetic and environmental modifiers (Gould et al 2007;Gould et al 2006). Mutations affecting the Y residue of the G-X-Y repeat or residues in the NC1 domain result in milder phenotypes than mutations affecting glycine residues (Favor et al 2007;Van Agtmael et al 2005). This difference was also observed at the BM level suggesting BM defects underlie the phenotypes (Van Agtmael et al 2005).…”

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

“…A simple loss-of-function mechanism is unlikely as mice heterozygous for COL4A1 and A2 null alleles exhibit no overt pathology, 75 whereas strains carrying both COL4A1 and A2 mutations show multiple defects including porencephaly, vascular abnormalities, and intracerebral hemorrhage. 37,76,77 Several mutually not exclusive neomorphic pathomechanisms have been proposed, which could explain the remarkable heterogeneity of disease symptoms ( Figure 2B). A variety of COL4A1/2 mutations have been shown to result in intracellular accumulation of mutant heterotrimers and in the activation of endoplasmic reticulum stress.…”