Mild recessive mutations in six fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract

Stefan Kohl, Daw Yang Hwang, Gabriel C. Dworschak, Alina C. Hilger, Pawaree Saisawat, Asaf Vivante, Natasa Stajic, Radovan Bogdanovic, Heiko M. Reutter, Elijah O. Kehinde, Velibor Tasic, Friedhelm Hildebrandt

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Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, .>90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.

Original languageEnglish
Pages (from-to)1917-1922
Number of pages6
JournalJournal of the American Society of Nephrology
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 1 2014

ASJC Scopus subject areas

  • Nephrology

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    Kohl, S., Hwang, D. Y., Dworschak, G. C., Hilger, A. C., Saisawat, P., Vivante, A., Stajic, N., Bogdanovic, R., Reutter, H. M., Kehinde, E. O., Tasic, V., & Hildebrandt, F. (2014). Mild recessive mutations in six fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. Journal of the American Society of Nephrology, 25(9), 1917-1922. https://doi.org/10.1681/ASN.2013101103