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Background COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies in humans. However, the causative genes for a number of hereditary multicystic kidney diseases, myopathies with cramps, and heritable intracranial aneurysms remain unknown.
Methods We characterized the renal and extrarenal phenotypes of subjects from three families who had an autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), which we propose is a syndrome. Linkage studies involving microsatellite markers flanking the COL4A1–COL4A2 locus were performed, followed by sequence analysis of COL4A1 complementary DNA extracted from skin-fibroblast specimens from the subjects.
Results We identified three closely located glycine mutations in exons 24 and 25 of the gene COL4A1, which encodes procollagen type IV
Conclusions COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.
1. The clinical renal manifestations of the HANAC syndrome in these families include hematuria and bilateral, large cysts. Histologic analysis revealed complex basement-membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appears to affect both small vessels and large arteries.
Source Information
From INSERM Unité 702 (E.P., B. Mougenot, M.C.V., P.R.); Université Pierre et Marie Curie, Paris 6, Unités Mixtes de Recherche Scientifique 702 (E.P., M.C.V., P.R.) and 582 (M.F.); Assistance Publique–Hôpitaux de Paris, Hôpital Tenon (E.P., S.A., B. Marro, E.R., P.R.), Hôpital Avicenne (C.P.), Hôpital Pitié–Salpêtrière (M.F.), and Hôpital Necker (C.A.); INSERM Unité 574 (O.G., C.A.); Center of Ophthalmology, Paris 15 (S.Y.C.); INSERM Unité 582 (M.F.); and Université Paris Descartes, Faculté de Médecine René Descartes, Unité Mixte de Recherche Scientifique 574 (C.A.) — all in Paris; Université Lille 2 (T.D.) and Centre Hospitalier Régional Universitaire Lille (M.D.) — both in Lille, France; University of Edinburgh, Queens Medical Research Institute, Edinburgh (T.V.A.); and Medical University of Vienna, Clinical Institute of Pathology, Vienna (D.K.).
Address reprint requests to Dr. Plaisier at the Department of Nephrology and INSERM Unité 702, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France, or at emmanuelle.plaisier{at}tnn.aphp.fr.
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