Autosomal recessive Alport's syndrome and benign familial hematuria are collagen type IV diseases.
BACKGROUND
Alport's syndrome (AS) is a genetically heterogeneous renal hereditary disease. Mutations in collagen type IV genes have been described to be responsible for X-linked (COL4A5), autosomal recessive, and autosomal dominant AS (COL4A3/COL4A4). Moreover, at least 40% of benign familial hematuria (BFH) cases cosegregate with the COL4A3/COL4A4 loci, following a dominant pattern of inheritance. Therefore, it has been suggested that BFH may represent the carrier state for autosomal recessive AS.


METHODS
We report a mutational study of the COL4A3 and COL4A4 genes in 14 AS and 2 BFH families. When possible, linkage analysis has been performed to confirm the pattern of inheritance. One affected proband from each family underwent mutation screening by single-strand conformation polymorphism/heteroduplex analysis.


RESULTS
We identified 13 mutations within the COL4A3 gene and 2 mutations within the COL4A4 gene, 9 of which are first reported here. We also detected 14 polymorphisms within the COL4A3 gene and 15 polymorphisms within the COL4A4 gene, 7 of them not previously described. In 2 of our AS families, we found mutations previously reported for BFH, and we characterized a novel mutation shared by an AS and a BFH family.


CONCLUSIONS
Collagen type IV nephropathy is an entity in itself, and phenotypic manifestations of COL4A3/COL4A4 mutations may range from monosymptomatic hematuria (BFH) to severe renal failure (AS), depending on the gene dosage. In 3 of our families, we genetically confirmed that BFH represents the carrier state for autosomal recessive AS.
Tazón Vega
Bárbara
B
Laboratory Department, Molecular Biology Laboratory, Fundació Puigvert, Barcelona, Spain.
Badenas
Cèlia
C
Ars
Elisabet
E
Lens
Xose
X
Milà
Montse
M
Darnell
Alejandro
A
Torra
Roser
R
D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D005808:Genes, Recessive; D008040:Genetic Linkage; D006417:Hematuria / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009394:Nephritis, Hereditary / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
D001324:Autoantigens; C466620:COL4A4 protein, human; C478159:COL4A5 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain