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
| Autor: | Kai-Olaf Netzer, Romy Lambrecht, Manfred Weber, Oliver Gross, Stefan Seibold |
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| Rok vydání: | 2003 |
| Předmět: |
Thin basement membrane disease
Adult Collagen Type IV Male Adolescent Genotype Genetic Linkage DNA Mutational Analysis Molecular Sequence Data Nephritis Hereditary Consanguinity Compound heterozygosity Kidney Type IV collagen Exon Germany medicine Humans Alport syndrome Hematuria Genetics Transplantation business.industry Reverse Transcriptase Polymerase Chain Reaction Point mutation Genetic disorder medicine.disease Pedigree Phenotype Nephrology Female business Gene Deletion |
| Zdroj: | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 18(6) |
| ISSN: | 0931-0509 |
| Popis: | 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 COL4A3u 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 a4(IV) cDNA. The daughter (15 years old, creatinine clearence 27 mlumin, proteinuria 5 guday, hearing loss) was homozygous for the mutation, while the son (22 years old, creatinine clearance 68 mlumin, proteinuria 11 guday, 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 BFHphenotype 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. |
| Databáze: | OpenAIRE |
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