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Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract.
J Am Soc Nephrol 2014; 25(9):1917-22JA

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 in 574 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.

Authors+Show Affiliations

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Institute of Human Genetics, and.Institute of Human Genetics, and Department of Pediatrics, University of Michigan, Ann Arbor, Michigan;Department of Pediatrics, University of Michigan, Ann Arbor, Michigan;Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;Medical Faculty, University of Belgrade, Belgrade, Serbia; Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia;Medical Faculty, University of Belgrade, Belgrade, Serbia; Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia;Institute of Human Genetics, and Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany;Department of Surgery, Kuwait University, Safat, Kuwait;Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia; and.Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland friedhelm.hildebrandt@childrens.harvard.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24700879

Citation

Kohl, Stefan, et al. "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, 2014, pp. 1917-22.
Kohl S, Hwang DY, Dworschak GC, et al. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2014;25(9):1917-22.
Kohl, S., Hwang, D. Y., Dworschak, G. C., Hilger, A. C., Saisawat, P., Vivante, A., ... 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, 25(9), pp. 1917-22. doi:10.1681/ASN.2013101103.
Kohl S, et al. Mild Recessive Mutations in Six Fraser Syndrome-related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract. J Am Soc Nephrol. 2014;25(9):1917-22. PubMed PMID: 24700879.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2014/04/03/ PY - 2014/4/5/entrez PY - 2014/4/5/pubmed PY - 2014/12/15/medline KW - CAKUT KW - FRAS1 KW - FREM1 KW - FREM2 KW - Fraser syndrome KW - GDNF KW - GREM1 KW - GRIP1 KW - ITGA8 KW - RET KW - VUR KW - genetic kidney disease KW - renal agenesis SP - 1917 EP - 22 JF - Journal of the American Society of Nephrology : JASN JO - J. Am. Soc. Nephrol. VL - 25 IS - 9 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 in 574 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. SN - 1533-3450 UR - https://www.unboundmedicine.com/medline/citation/24700879/Mild_recessive_mutations_in_six_Fraser_syndrome_related_genes_cause_isolated_congenital_anomalies_of_the_kidney_and_urinary_tract_ L2 - http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=24700879 DB - PRIME DP - Unbound Medicine ER -