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
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (R01- DK045345 and R01-DK088767 to F.H.). F.H. is an investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and a Warren E. Grupe Professor.
Funding Information:
The authors thank the affected individuals, their families, and their physicians who contributed to this study. This work was supported by grants from the National Institutes of Health (R01-DK045345 and R01-DK088767 to F.H.). F.H. is an investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and a Warren E. Grupe Professor.
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.
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U2 - 10.1681/ASN.2013101103
DO - 10.1681/ASN.2013101103
M3 - Article
C2 - 24700879
AN - SCOPUS:84921669891
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 -