COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps

The collagen genes COL4A3, COL4A4, and COL4A5 have been implicated in inherited nephropathies. The authors show that glycine mutations in COL4A1, which encodes procollagen type IV α1, result in autosomal dominant hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC). Thus, COL4A1 mutations should be sought in patients who have unexplained familial syndromes with these features. Glycine mutations in COL4A1, which encodes procollagen type IV α1, result in autosomal dominant hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC). Six alpha chains of type IV collagen — α1(IV) through α6(IV) — produce three networks of type IV collagen: α1.α1.α2(IV), α3.α4.α5(IV), and α5.α5.α6(IV). These three networks are the main component of basement membranes. Alpha chains of type IV collagen consist of an N-terminal 7S domain; a triple-helical collagenous domain, containing the classic Gly–Xaa–Yaa repeat amino acid sequence; and a C-terminal noncollagenous NC1 domain. 1 The α1.α1.α2(IV) network is widely expressed in the body, whereas the α3.α4.α5(IV) and α5.α5.α6(IV) networks have a tissue-restricted expression. In the kidney, the α3.α4.α5(IV) network replaces the α1.α1.α2(IV) network during embryogenesis of the glomerular basement membrane, whereas . . .