Nephrol Dial Transplant (2003) 18: 1122-1127
© 2003 European Renal Association-European Dialysis and Transplant Association
Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome
Medical Faculty University of Cologne, Cologne General Hospital, Department of Internal Medicine I, Merheim Medical Center, Cologne, Germany
Background. Alport syndrome (AS) is a common hereditary cause for end-stage renal failure due to a defect in type IV collagen genes. The molecular pathogenesis of benign familial haematuria (BFH) is not fully understood. Evidence from linkage analyses and mutation studies point to a role of the COL4A3/COL4A4 genes. The present study describes molecular changes of the COL4A4 gene that cause both diseases: autosomal recessive AS and BFH in a consanguine family with a 400-year-old history of haematuria.
Methods. RNA and DNA were isolated and analysed by RT–PCR, PCR, DNA and cDNA sequencing, and Southern blotting. Evaluation of family members comprised creatinine clearence, urine analysis, audiometry and past medical history.
Results. Forefathers of this family moved to a German village in the 17th century. Sporadic episodes of macrohaematuria have been reported ever since. Numerous family members with haematuria including the parents of the index family were heterozygous for a splice defect eliminating exon 25 from the 
4(IV) cDNA. The daughter (15 years old, creatinine clearence 27 ml/min, proteinuria 5 g/day, hearing loss) was homozygous for the mutation, while the son (22 years old, creatinine clearance 68 ml/min, proteinuria 11 g/day, hearing loss, splitted and thickened glomerular basement membrane) was heterozygous. Further analysis showed a second mutation, an 18 bp in-frame deletion in exon 25, for which numerous family members were heterozygous, and both children were homozygous.
Conclusions. The COL4A4 splice defect causes BFH-phenotype in heterozygous, and AS in homozygous state. The clinical spectrum of heterozygous individuals reaches from macrohaematuria, intermittent microhaematuria to isolated deafness. The 18 bp in-frame deletion aggravates the phenotype in the compound heterozygous son. These results give further evidence that BFH and autosomal AS are in fact both type IV collagen diseases.
Keywords: deafness; extracellular matrix; genetic disorder; kidney failure chronic; thin glomerular basement membrane disease; type IV collagen
Correspondence and offprint requests to: Dr Oliver Gross, Medical Faculty University of Cologne, Cologne General Hospital, Merheim Medical Center, Department of Internal Medicine I, Ostmerheimer Strasse 200, D-51109 Cologne, Germany. Email: oliver.gross{at}uni\|[hyphen]\|koeln.de
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