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

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 : JASN
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 1 2014
Externally publishedYes

Fingerprint

Fraser Syndrome
Mutation
Genes
Recessive Genes
Cakut
Mesoderm
Missense Mutation
Chronic Kidney Failure
Exons

ASJC Scopus subject areas

  • Nephrology

Cite this

Mild recessive mutations in six fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. / Kohl, Stefan; Hwang, Daw Yang; Dworschak, Gabriel C.; Hilger, Alina C.; Saisawat, Pawaree; Vivante, Asaf; Stajic, Natasa; Bogdanovic, Radovan; Reutter, Heiko M.; Kehinde, Elijah O.; Tasic, Velibor; Hildebrandt, Friedhelm.

In: Journal of the American Society of Nephrology : JASN, Vol. 25, No. 9, 01.09.2014, p. 1917-1922.

Research output: Contribution to journalArticle

Kohl, S, Hwang, DY, Dworschak, GC, Hilger, AC, Saisawat, P, Vivante, A, Stajic, N, Bogdanovic, R, Reutter, HM, Kehinde, EO, 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 : JASN, vol. 25, no. 9, pp. 1917-1922. https://doi.org/10.1681/ASN.2013101103
Kohl, Stefan ; Hwang, Daw Yang ; Dworschak, Gabriel C. ; Hilger, Alina C. ; Saisawat, Pawaree ; Vivante, Asaf ; Stajic, Natasa ; Bogdanovic, Radovan ; Reutter, Heiko M. ; Kehinde, Elijah O. ; Tasic, Velibor ; Hildebrandt, Friedhelm. / Mild recessive mutations in six fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. In: Journal of the American Society of Nephrology : JASN. 2014 ; Vol. 25, No. 9. pp. 1917-1922.
@article{398d9a20053645dd9a417a3de605f526,
title = "Mild recessive mutations in six fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract",
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.",
author = "Stefan Kohl and Hwang, {Daw Yang} and Dworschak, {Gabriel C.} and Hilger, {Alina C.} and Pawaree Saisawat and Asaf Vivante and Natasa Stajic and Radovan Bogdanovic and Reutter, {Heiko M.} and Kehinde, {Elijah O.} and Velibor Tasic and Friedhelm Hildebrandt",
year = "2014",
month = "9",
day = "1",
doi = "10.1681/ASN.2013101103",
language = "English",
volume = "25",
pages = "1917--1922",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "9",

}

TY - JOUR

T1 - Mild recessive mutations in six fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract

AU - Kohl, Stefan

AU - Hwang, Daw Yang

AU - Dworschak, Gabriel C.

AU - Hilger, Alina C.

AU - Saisawat, Pawaree

AU - Vivante, Asaf

AU - Stajic, Natasa

AU - Bogdanovic, Radovan

AU - Reutter, Heiko M.

AU - Kehinde, Elijah O.

AU - Tasic, Velibor

AU - Hildebrandt, Friedhelm

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84921669891&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921669891&partnerID=8YFLogxK

U2 - 10.1681/ASN.2013101103

DO - 10.1681/ASN.2013101103

M3 - Article

VL - 25

SP - 1917

EP - 1922

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 9

ER -