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.

Figure 1

Pedigrees and COL4A2 Mutations in Individuals 1 and 2 Pedigrees of family 1(A) and family 2 (B). The arrows indicate the probands (Individual 1 in family 1 and individual 2 in family 2). The segregation of the COL4A2 mutations is shown. In family 1, the proband's mother (III-2) and maternal uncle (III-1) had mild monoparesis of the left upper extremity and congenital left hemiplegia and an assisted walk, respectively. The maternal grandfather (II-7) was healthy. The elder granduncle (II-5) was also afflicted by congenital hemiplegia and died in his 60s. (B) In family 2, the proband had a heterozygous mutation, but his parents did not have this mutation, indicating that the mutation occurred de novo. His elder sister (II-2) had intraventricular hemorrhage two days after birth but her DNA was unavailable. (C) Electropherogram of family 1 (left) and family 2 (right). The intron and exon bases are in lower and upper cases, respectively. The c.3455G>A (p.Gly1152Asp) mutation in individual 1 was inherited from his mother. The c.3110G>A (p.Gly1037Glu) mutation in individual 2 occurred de novo. (D) Multiple amino acid sequence alignments of COL4A2 proteins showing the evolutionarily conserved amino acids. The protein sequences obtained from the National Center for Biotechnology Information protein database are, NP_001837.2 (Homo sapiens), NP_034062.3 (Mus musculus), NP_001155862.1 (Gallus gallus), XP_002933063.1 (Xenopus tropicalis), XP_687811.5 (Danio rerio), AAB64082.1 (Drosophila melanogaster), and CAA80537.1 (Caenorhabditis elegans). The multiple sequence alignment was performed via the CLUSTALW website (see Web Resources). The positions of the conserved Gly residues in the Gly-X-Y repeats where the mutations occurred are highlighted with gray.

Figure 2

Brain Imaging in Individuals 1 and 2 (A–C) Brain MRIs of individual 1 at 6 years old; (A) T2-weighted axial image. (B) Coronal image. The images in (A) and (B) show an enlarged right lateral ventricle and a reduced volume of the right frontal white matter. (C) T1-weighted midline sagittal image showing atrophy of the body of the corpus callosum (arrowheads). The lesion responsible for the left leg paresis is not evident in these images. (D–F) Brain MRIs of individual 1's mother at age 31. (D) T2-weighted axial and (F) coronal images show a mildly enlarged right lateral ventricle. (E) FLAIR axial image shows high signal intensity around the enlarged ventricular wall, which is consistent with mild porencephaly or periventricular venous infarction. (G–I) CT images of individual 2 at 2 months of age. (G) Axial image. (H) Coronal image. (I) Sagittal image. The images in (G), (H), and (I) show an enlarged bilateral lateral ventricle and an extremely reduced volume of bilateral frontal white matter. The V-P shunt tube is also visible in the right lateral ventricle. The pontocerebellar structures seem to be normal.