Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract.
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.
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
Stefan
S
Kohl
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;
Daw-Yang
DY
Hwang
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Institute of Human Genetics, and.
Gabriel C
GC
Dworschak
Institute of Human Genetics, and Department of Pediatrics, University of Michigan, Ann Arbor, Michigan;
Alina C
AC
Hilger
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan;
Pawaree
P
Saisawat
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
Asaf
A
Vivante
Medical Faculty, University of Belgrade, Belgrade, Serbia; Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia;
Natasa
N
Stajic
Medical Faculty, University of Belgrade, Belgrade, Serbia; Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia;
Radovan
R
Bogdanovic
Institute of Human Genetics, and Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany;
Heiko M
HM
Reutter
Department of Surgery, Kuwait University, Safat, Kuwait;
Elijah O
EO
Kehinde
Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia; and.
Velibor
V
Tasic
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland friedhelm.hildebrandt@childrens.harvard.edu.
Friedhelm
F
Hildebrandt
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D000013:Congenital Abnormalities / Q000235:genetics; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D058497:Fraser Syndrome / Q000235:genetics*; D005808:Genes, Recessive; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007668:Kidney / Q000002:abnormalities*; D007674:Kidney Diseases / Q000151:congenital / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics*; D014551:Urinary Tract / Q000002:abnormalities*; D014564:Urogenital Abnormalities; D014718:Vesico-Ureteral Reflux / Q000235:genetics*
D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; C475145:FRAS1 protein, human; C500786:FREM2 protein, human; C548979:Frem1 protein, human; C486399:GREM1 protein, human; C491310:GRIP1 protein, human; C579157:ITGA8 protein, human; D039001:Integrin alpha Chains; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018123:Receptors, Interleukin
CAKUT; FRAS1; FREM1; FREM2; Fraser syndrome; GDNF; GREM1; GRIP1; ITGA8; RET; VUR; genetic kidney disease; renal agenesis