De Novo and Inherited Mutations in COL4A2, Encoding the Type IV Collagen α2 Chain Cause Porencephaly

Abstract

Porencephaly is a neurological disorder characterized by fluid-filled cysts or cavities in the brain that often cause hemiplegia. It has been suggested that porencephalic cavities result from focal cerebral degeneration involving hemorrhages. De novo or inherited heterozygous mutations in COL4A1, which encodes the type IV α1 collagen chain that is essential for structural integrity for vascular basement membranes, have been reported in individuals with porencephaly. Most mutations occurred at conserved Gly residues in the Gly-Xaa-Yaa repeats of the triple-helical domain, leading to alterations of the α1α1α2 heterotrimers. Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain. Mutations c.3455G>A and c.3110G>A, one in each of the individuals, cause Gly residues in the Gly-Xaa-Yaa repeat to be substituted as p.Gly1152Asp and p.Gly1037Glu, respectively, probably resulting in alterations of the α1α1α2 heterotrimers. The c.3455G>A mutation was found in the proband's mother, who showed very mild monoparesis of the left upper extremity, and the maternal elder uncle, who had congenital hemiplegia. The maternal grandfather harboring the mutation is asymptomatic. The c.3110G>A mutation occurred de novo. Our study confirmed that abnormalities of the α1α1α2 heterotrimers of type IV collagen cause porencephaly and stresses the importance of screening for COL4A2 as well as for COL4A1.

The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature

“…For this, a PubMed search was performed, identifying 27 articles with clinical and mutation data on COL4A1 7,8,[10][11][12][13][14][15][16][17][18][19][20][21][22][29][30][31][32][33][34][35][36][37][38][39][40] and 3 articles with data on COL4A2 mutations. [26][27][28] A total of 137 individuals with a COL4A1 mutation from 60 families and 15 individuals with a COL4A2 mutation from 7 families have been reported. Several clinical phenotypes were identified and described in more detail.…”

“…In 2012 several parallel genetic, epidemiologic, and functional studies revealed COL4A2 mutations in both familial and sporadic porencephaly. [26][27][28] The disease resulting from both COL4A1 and COL4A2 mutations is extremely variable, with broad intra-and interfamilial variation and evidence for reduced penetrance. Sporadic individuals with severe presentation may harbor a de novo mutation.…”

Familial Brain Periventricular Pseudocysts

“…The possibility of diseases not expected to be diagnosed early in life or with variable phenotypic presentations needs to be considered. An example of this kind of disease may be the disorder caused by mutations in COL4A1/COL4A2, which is associated with white matter anomalies and periventricular cysts, but can remain asymptomatic until late in life [15] . Since the number of familial cases with PVPC diagnosed in utero is small and we have not been able to diagnose a genetic etiology, at present we are not able to exclude a possible coincidental occurrence.…”

Postnatal diagnosis of constitutive ring chromosome 13 using both conventional and molecular cytogenetic approaches

“…Moreover, deletions of COL4A1 were first shown to cause porencephaly, cerebral hemorrhage, and microangiopathy in humans (Rodahl et al, 2013). Heterozygous mutations of COL4A2 have been associated with porencephaly 2 (OMIM 614483) (Yoneda et al, 2012) and increased nuchal translucency (Jeanne et al, 2012;Weng et al, 2012). Haploinsufficiency of COL4A1 and COL4A2 may be associated with susceptibility to intracerebral hemorrhage (OMIM 614519) (Jeanne et al, 2012;Weng et al, 2012) and increased nuchal translucency .…”