COL4A1Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps

Abstract

COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.

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.…”

“…Whether the tachycardia is causally related to the COL4A1 mutation is unclear; however, it has also been reported in hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome. 16 …”

“…16,32,35 The angiopathy in HANAC syndrome comprises retinal vessel arterial tortuosity and cerebral small-and large-vessel disease with aneurysms of the carotid syphon. The nephropathy consists of persistent hematuria and/ or proteinuria with or without bilateral large renal cysts.…”

“…Also, the risk of major (hemorrhagic) stroke is thought to be lower than in other COL4A1 mutations. 16,32,35 In our cohort, no patients displaying the HANAC phenotype were identified, possibly because of referral bias, since our cohort comprises mostly neurological patients. The clinical picture of HANAC is possibly insufficiently known by referring physicians to be associated with COL4A1 mutations.…”

“…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. [10][11][12][13][14][15][16][17][18][19][20][21][22] COL4A1 and COL4A2 encode proα1(IV) and proα2(IV) chains, respectively, which assemble to form a heterotrimeric helix with a constant 2:1 ratio (proα1(IV)) 2 (proα2 (IV)). This type IV collagen is a component of nonfibrillary collagen, a main constituent of the basement membranes of many tissues, among them vascular endothelia.…”