COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.
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 alpha1. 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.


CONCLUSIONS
COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.
Plaisier
Emmanuelle
E
INSERM Unité 702, Université Pierre et Marie Curie, Paris 6, Unités Mixtes de Recherche Scientifique 702, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, France. emmanuelle.plaisier@tnn.aphp.fr
Gribouval
Olivier
O
Alamowitch
Sonia
S
Mougenot
Béatrice
B
Prost
Catherine
C
Verpont
Marie Christine
MC
Marro
Béatrice
B
Desmettre
Thomas
T
Cohen
Salomon Yves
SY
Roullet
Etienne
E
Dracon
Michel
M
Fardeau
Michel
M
Van Agtmael
Tom
T
Kerjaschki
Dontscho
D
Antignac
Corinne
C
Ronco
Pierre
P
D000015:Abnormalities, Multiple / Q000235:genetics*; D001485:Basement Membrane / Q000473:pathology; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics; D006417:Hematuria / Q000235:genetics; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology; D008297:Male; D009120:Muscle Cramp / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D014652:Vascular Diseases / Q000235:genetics*
D024141:Collagen Type IV