Klin Padiatr 2011; 223 - P063
DOI: 10.1055/s-0031-1273864

High proportion of novel mutations in patients with Alport syndrome

J Höfele 1, S Weber 2, S Rath 1, I Rost 1, HG Klein 1
  • 1Zentrum für Humangenetik und Laboratoriumsmedizin Dr. Klein und Dr. Rost, Martinsried
  • 2Klinik für Kinder- und Jugendheilkunde 2, Universitätsklinikum Essen, Essen

Alport syndrome (AS) is characterized by ultrastructural abnormalities of the glomerular basement membrane (GBR) with progression to end-stage renal disease (ESRD), eye abnormalities and high-tone sensorineural deafness [1]. Mutations in COL4A3 and COL4A4 genes can be associated with an autosomal recessive or dominant type, whereas mutations in COL4A5 cause X-linked AS. The X-linked form predominantly affects male individuals, female patients have mild symptoms [2]. In comparison to AS, the autosomal dominant inherited thin basement membrane nephropathy (TBMN) is characterized by persistent glomerular hematuria, minimal proteinuria and normal renal function. Mutations have been identified in COL4A3 and COL4A4 [3].

In order to detect the relative frequency of novel COL4A3, COL4A4, and COL4A5 mutations in our study population we examined 19 AS families and 3 TBMN families collected over 1 year. All AS patients were tested for mutations/deletions in COL4A5, COL4A4, and/or COL4A3 dependent on the family history. The TBMN patients were screened for mutations in COL4A3 and COL4A4. Furthermore, the frequency of female patients with X-linked AS were analyzed.

In a large proportion of the investigated families novel mutations could be found (15/22 families; 68%). Altogether, we have detected mutations in 19 families: COL4A3 mutations in 3 AS families and in one TBMN family (18%), COL4A4 mutations in one TBMN family (4%), and COL4A5 mutation/deletions in 14 AS families (64%). In two AS families and one family with microhematuria no mutation was found (14%). 12/19 families had glycine mutations (63%). A high detection rate of 86% was achieved. 36% of patients with X-linked AS were female (5/14 patients).

We have found relevant mutations for AS in most of our patients identifying a high number of novel mutations. The increased number of known mutations will facilitate future studies into genotype-phenotype correlations. The frequency of female patients with X-linked AS is higher as described in the literature.

Alport syndrome - mutational analysis - thin basement nephropathy