Mutations in Col4a1 Cause Perinatal Cerebral Hemorrhage and Porencephaly

Abstract

Porencephaly is a rare neurological disease, typically manifest in infants, which is characterized by the existence of degenerative cavities in the brain. To investigate the molecular pathogenesis of porencephaly, we studied a mouse mutant that develops porencephaly secondary to focal disruptions of vascular basement membranes. Half of the mutant mice died with cerebral hemorrhage within a day of birth, and approximately 18% of survivors had porencephaly. We show that vascular defects are caused by a semidominant mutation in the procollagen type IV alpha 1 gene (Col4a1) in mice, which inhibits the secretion of mutant and normal type IV collagen. We also show that COL4A1 mutations segregate with porencephaly in human families. Because not all mutant mice develop porencephaly, we propose that Col4a1 mutations conspire with environmental trauma in causing the disease.

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.…”

“…The first reports suggested an onset around birth, 8 whereas later reports also describe patients with an onset during late pregnancy. 12,21,29 In our cohort, 12 patients from 10 families (A, B, D, E, G, H, I, J, K, M) presented with early intracerebral hemorrhage and Recurrence of cerebral hemorrhage was documented in patient E-II.1, who presented with antenatal cerebral hemorrhage and porencephaly on antenatal brain MRI.…”

“…Porencephaly is one of the most frequently reported findings, described in 53 patients with COL4A1 mutations 7,8,12,14,15,17,18,21,[37][38][39] and 6 patients with COL4A2 mutation 27,28 ( Table 2). Because porencephaly was the first reported associated phenotype, however, there may be a bias in the inclusion of patients for COL4A1 and COL4A2 testing.…”

“…Only in 2005, after observations of mouse models, were COL4A1 mutations discovered as a cause of porencephaly, with an apparent autosomal dominant inheritance. [7][8][9] Over the years it became clear that disorders of additional organs can result from mutations in this gene. The disorder related to COL4A1 mutations is now known as a systemic disease, including a broad spectrum of cerebrovascular lesions: porencephaly and transmantle lesions, causing hydranencephaly or schizencephaly; lesions of the kidneys, leading to nephrosis and hematuria; lesions of the eyes, causing cataract, microphthalmia, and blindness; lesions of the heart, causing arrhythmia; and lesions of the skeletal muscles, causing dystrophic changes, weakness, and myoglobinuria.…”

Genomic analysis identifies masqueraders of full‐term cerebral palsy

“…To our knowledge, no genetic studies have specifically focused on full‐term CP. In addition, brain MRI findings are essential for correctly assessing CP by excluding cases caused by apparent environmental factors or cases with other disorders5 (e.g., porencephaly with COL4A1 variants7 and cerebral infarction with CBS variants8) for which other diagnostic approaches could be used, such as metabolic screening and target sequencing.…”