Format

Send to

Choose Destination
J Am Soc Nephrol. 2014 Sep;25(9):1917-22. doi: 10.1681/ASN.2013101103. Epub 2014 Apr 3.

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

Author information

1
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
2
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;
3
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Institute of Human Genetics, and.
4
Institute of Human Genetics, and Department of Pediatrics, University of Michigan, Ann Arbor, Michigan;
5
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan;
6
Medical Faculty, University of Belgrade, Belgrade, Serbia; Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia;
7
Institute of Human Genetics, and Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany;
8
Department of Surgery, Kuwait University, Safat, Kuwait;
9
Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia; and.
10
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland friedhelm.hildebrandt@childrens.harvard.edu.

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.

KEYWORDS:

CAKUT; FRAS1; FREM1; FREM2; Fraser syndrome; GDNF; GREM1; GRIP1; ITGA8; RET; VUR; genetic kidney disease; renal agenesis

PMID:
24700879
PMCID:
PMC4147986
DOI:
10.1681/ASN.2013101103
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center