title: Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain.
abstract: The COL4A1 gene encodes the α1-chain of type IV collagen, which is ubiquitously expressed in basement membranes. Mutations in COL4A1 have been reported in autosomal-dominant porencephaly and in patients with symptomatic small vessel brain disease, inconstantly associated with eye defects. We have previously reported three COL4A1 mutations associated with a systemic phenotype that we called HANAC (Hereditary Angiopathy, Nephropathy, Aneurysms, and Cramps). We carried out a clinical and genetic study of three families presenting with characteristic features of HANAC syndrome. Common systemic signs included arterial retinal tortuosity and muscle cramps, with a variable combination of small vessel brain disease, Raynaud phenomena, and kidney defects. Three novel COL4A1 missense substitutions are described, which affect highly conserved glycine residues within the collagenous domain of the protein. All six known mutations associated with the HANAC phenotype are localized within the CB3[IV] fragment of COL4A1, which encompasses major integrin-binding sites. Our results confirm that HANAC syndrome is a distinct clinical entity within the COL4A1-related disorders, which is characterized by systemic involvement and usually asymptomatic brain disease. The restricted distribution of COL4A1 mutations within the CB3[IV] region is a characteristic of the reports of patients with HANAC, which suggests that abnormal cell-type IV collagen interactions may underlie the systemic defects observed in this syndrome.
authors.affiliation: AP HP, Department of Nephrology, Tenon Hospital, INSERM U702, UMRS702, Université Pierre et Marie Curie-Paris 6, Paris, France. emmanuelle.plaisier@tnn.aphp.fr
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Plaisier
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Chen
authors.forename: Florian
authors.initials: F
authors.lastname: Gekeler
authors.forename: Safa
authors.initials: S
authors.lastname: Benhassine
authors.forename: Karine
authors.initials: K
authors.lastname: Dahan
authors.forename: Béatrice
authors.initials: B
authors.lastname: Marro
authors.forename: Sonia
authors.initials: S
authors.lastname: Alamowitch
authors.forename: Michel
authors.initials: M
authors.lastname: Paques
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001927:Brain Diseases / Q000235:genetics; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics*; D017124:Conserved Sequence; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011928:Raynaud Disease / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV