NDT Advance Access originally published online on January 7, 2009
Nephrology Dialysis Transplantation 2009 24(5):1464-1471; doi:10.1093/ndt/gfn681
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Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome
1 Medical Genetics, Department of Molecular Biology, University of Siena, Italy 2 Clinical Genetic Unit, Department of Pediatrics, University of Turin, Italy 3 Department of Pediatrics, M. Bufalini Hospital, Cesena, Italy 4 Nephrology and Dialysis Units, Azienda Ospedaliera Careggi, Florence, Italy 5 Transplantation Immunology, San Giovanni Battista Hospital, Torino, Italy 6 Nephrology and Dialysis Units, Ospedale di Cirié, Cirié, Italy 7 Department of Pediatrics, IRCCS Burlo Garofolo Trieste, Trieste, Italy 8 Department of Clinical and Biological Sciences, Division of Medical Genetics, University of Turin, Orbassano, Italy 9 Nephrology and Dialysis Units, S. Andrea Hospital, La Spezia, Italy 10 Nephrology and Dialysis Units, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy 11 Department of Biomedical Sciences and Biotechnology, University of Cagliari, Italy 12 Department of Medical Genetics, RDO Medical Diagnosis, São Paulo, Brazil 13 Transplantation Surgery, University of Siena, Siena, Italy
Correspondence and offprint requests to: Alessandra Renieri, Medical Genetics, Department of Molecular Biology, University of Siena, V.Le Bracci, 53100 Siena, Italy. Tel: +39-0577-233303; Fax: +39-0577-233325; E-mail: renieri{at}unisi.it
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Abstract |
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Background. Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane lesions often associated with hearing loss and ocular anomalies. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged.
Methods. We have clinically investigated 38 patients with a diagnosis of autosomal dominant Alport syndrome belonging to eight different families. The analysis of the COL4A4 gene was performed by denaturing high performance liquid chromatography and automated DNA sequencing.
Results. In our cohort of patients, only 24.3% (9/37) reached end-stage renal disease, at the mean age of 51.2 years. Four patients had hearing loss (13.3%) and none ocular changes. Molecular analysis revealed eight novel private COL4A4 gene mutations: three frameshift, three missense and two splice-site mutations.
Conclusions. These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal failure although at an older age than the X-linked form. We were unable to demonstrate a genotype–phenotype correlation. Altogether, these data make difficult the differential diagnosis with the benign familial haematuria due to heterozygous mutations of COL4A4 and COL4A3, especially in young patients, and with the X-linked form of Alport syndrome in families where only females are affected. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible associated with a broadly formal genetic analysis of the pedigree.
Keywords: ADAS; ATS; autosomal dominant Alport syndrome; BFH; COL4A4; TBMN
Received for publication: 3. 9.08
Accepted in revised form: 14.11.08
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