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.