Clinical Investigation

Kidney International (1993) 44, 1091–1096; doi:10.1038/ki.1993.353

Identification of a single base insertion in the COL4A5 gene in Alport syndrome

Hitoshi Nakazato, Shinzaburo Hattori, Toshinobu Matsuura, Yasushi Koitabashi, Fumio Endo and Ichiro Matsuda

Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto, and Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan

Correspondence: Ichiro Matsuda MD PhD, Department of Pediatrics, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860, Japan.

Received 16 November 1992; Revised 11 May 1993; Accepted 7 June 1993.

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Abstract

Identification of a single base insertion in the COL4A5 gene in Alport syndrome. We identified a novel mutation in the COL4A5 gene of a Japanese patient with Alport syndrome. A combination of in vitro amplification of the exons with single strand conformation polymorphisms (SSCP) analysis suggested the presence of a mutation in exon 48. Sequencing of the amplified DNA revealed a single base (T) insertion which was between nucleotides T 4750 and G 4751 within the methionine 1516. This mutation caused a shift in the reading frame of nine amino acids and introduced a premature termination signal that would be expected to lack about two-thirds of the noncollagenous (NCI) domain. This mutation may interfere with type IV collagen assembly leading to increased permeability and play a causative role in the glomerular basement membrane abnormality of this patient with typical Alport syndrome. Gene tracking by restriction enzyme NlaIII digestion revealed that the patient's mother is heterozygous whereas the patient's brother and one sister are normal, albeit they have hematuria and proteinuria. Without gene analysis, they would have been misdiagnosed. We propose that the diagnosis of Alport syndrome should be made on the basis of both clinical phenotypes and molecular defects.

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