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 language | English |
|---|---|
| Pages (from-to) | 1917-1922 |
| Number of pages | 6 |
| Journal | Journal of the American Society of Nephrology : JASN |
| Volume | 25 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 1 2014 |
| Externally published | Yes |
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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 journal › Article
}
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.
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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 -