Abstract
The most frequent causes of chronic renal failure in the first two decades of life are due to urinary tract malformations. Branchio-oto-renal syndrome (BOR) [OMIM 113650] is an autosomal dominant developmental disorder of the kidney and urinary tract, accompanied with hearing loss and presenting with a wide intrafamilial variability and reduced penetrance. Dominant mutations in the human homologues of the Drosophila eyes absent gene (EYA1) are frequently the cause of BOR and BO syndromes. EYA1 encodes a 559-amino acid polypeptide with a predicted molecular mass of 61.2 kD. Mutational analysis revealed a novel nonsense mutation in EYA1 as the cause of BOR in this family.
Family JCA7 is of South African Caucasian descent and was identified during routine prenatal ultrasound screening. The proband (II.2) was noted to have absent kidneys and oligohydramnios during this initial screening. A review of the health histories of the family indicated a history of Potter Sequence in a previous pregnancy (II.3) and that the father (I.1) has a unilateral pre-auricular pit with ipsilateral hearing loss. Preliminary renal ultrasound scans of I.1, the mother (I.2) and unaffected daughter (II.1) did not reveal any abnormalities of the urogenital system. Post mortem analysis of II.2 indicated that a solitary dysplastic kidney was present. The infant also presented with a hypoplastic bladder, Potter facies and pulmonary hypoplasia. Based on this evidence we elected to do direct sequencing of the EYA1 gene for mutational analysis. (University of Michigan IRB # 2004–0322). Sequence analysis revealed that the patients I.1 and II.2 carried a heterozygous mutation (727GT) affecting the last coding nucleotide of exon 7. Translation of this mutation results in E243X that presumably truncates the full length EYA1 protein by the introduction of a stop codon. The E243X mutation in the affected members of this family should result in a protein product lacking the critical EYA homologous region (EYAhr) encoded by exons 9 through 16. The EYAhr is imperative for the ability of the EYA1 protein product to bind to other proteins, such as SIX1, and regulate transcription properly. Functional analysis is currently being performed in order to assess the mutational effect on binding of protein complex partners and DNA target sequences. Phenotype/genotype correlations are also being investigated as more samples from the kindred become available.
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Clarke, J., Honey, E., Raymond, R. et al. 18 Identification of a Novel Nonsense Mutation in the Eya1 Gene Associated with Branchiootic/Branchio-Oto-Renal Syndrome.. Pediatr Res 58, 819 (2005). https://doi.org/10.1203/00006450-200510000-00048
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DOI: https://doi.org/10.1203/00006450-200510000-00048