COL4A2 mutation associated with familial porencephaly and small-vessel disease

Abstract

Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 3206delC fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.

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

“…In analogy to other collagenopathies, these mutations are predicted to be pathogenic and are assumed to have a dominant-negative effect. In addition, splice-site mutations led to haploinsufficiency, and frameshift mutations have been reported, indicating that haploinsufficiency of either COL4A1 or COL4A2 is another pathogenic mechanism 27,38 (Figure 1). COL4A1 and COL4A2 sequence variants in our cohort were considered pathogenic when de novo, when truncating, or when previously described and were proven to be pathogenic by de novo occurrence or functional studies.…”

“…We previously reported two of the COL4A2 and nine of the COL4A1 mutations. 7,12,15,27,29 From the families with the remaining 13 novel mutations, clinical data were collected using a questionnaire sent to the referring physicians according to the institutional review board regulations of our center.…”

“…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.…”

Advances in Stroke

“…Mutations of the COL4A2 have now been reported to cause not only familial porencephaly but also small-vessel disease and hemorrhagic stroke in human patients. [13][14][15] Novel molecular genetics tools also recently led to the identification of several genes involved in other stroke conditions, such as moyamoya disease and monogenic moyamoya syndromes, opening avenues to understanding the mysteries of their pathophysiology. 16,17 Finally, it is helpful to inform patients that conventional modifiable risk factors remain relevant, despite an unfavorable genetic background.…”