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Clin Genet. 2015 Nov;88(5):462-7. doi: 10.1111/cge.12522. Epub 2014 Nov 10.

Collagen type IV-related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families.

Author information

1
Department of Genetics, Faculty of Medicine, Porto, Portugal.
2
Unit of Research and Development of Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal.
3
Department of Nephrology, Porto, Portugal.
4
Department of Otolaryngology, Porto, Portugal.
5
Medical Genetics Outpatient Clinic, Porto, Portugal.
6
Department of Ophthalmology, Hospital de São João, Porto, Portugal.
7
Department of Nephrology, Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal.
8
Department of Nephrology, Hospital dos Marmeleiros, Funchal, Portugal.
9
Department of Medical Genetics, Hospital Dona Estefânia, Lisboa, Portugal.
10
Dialysis Clinic of Santarém, NephroCare-Portugal, Santarém, Portugal.
11
Department of Nephrology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.
12
Department of Nephrology, Hospital de Braga, Braga, Portugal.
13
Dialysis Clinic of Restelo, NephroCare-Portugal, Lisboa, Portugal.
14
Dialysis Clinic of Santo Tirso, Uninefro, Santo Tirso, Portugal.
15
Department of Nephrology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
16
Department of Nephrology, Hospital de São Teotónio, Viseu, Portugal.
17
Dialysis Clinic of Guarda, NephroCare-Portugal, Guarda, Portugal.
18
Dialysis Clinic of Braga, NephroCare-Portugal, Braga, Portugal.
19
Department of Nephrology, Hospital Garcia de Orta, Almada, Portugal.
20
Department of Nephrology, Hospital de Faro, Faro, Portugal.
21
Dialysis Clinic of Montijo, NephroCare-Portugal, Montijo, Portugal.
22
Dialysis Clinic of Coimbra, NephroCare-Portugal, Coimbra, Portugal.
23
Department of Nephrology, Hospital de Santa Maria, Lisboa, Portugal.
24
Department of Nephrology, Hospital Amato Lusitano, Castelo Branco, Portugal.
25
Dialysis Clinic of Covilhã, NephroCare-Portugal, Covilhã, Portugal.
26
Dialysis Clinic of Lumiar, NephroCare-Portugal, Lisboa, Portugal.
27
Dialysis Clinic of Viseu, NephroCare-Portugal, Viseu, Portugal.
28
Unit of Renal Morphology, Department of Nephrology, Hospital Curry Cabral, Lisboa, Portugal.

Abstract

Alport syndrome (AS) is caused by pathogenic mutations in the genes encoding α3, α4 or α5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next-generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first-tier approach to the genetic diagnosis of collagen type IV-related nephropathies.

KEYWORDS:

COL4A5 mutations; Portuguese population; X-linked Alport syndrome; genotype-phenotype correlation

PMID:
25307721
DOI:
10.1111/cge.12522
[Indexed for MEDLINE]

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