BACKGROUND: Bilateral renal agenesis (BRA) is a lethal con genital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios on fetal ultrasonography reveals BRA. Although the exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics do not pick up many clinical patients. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development, and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia. METHODS: A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy, due to suspected BRA. Whole-exome sequencing (WES)-based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype. RESULTS: WES and evaluation of homozygous regions in II:3 and II:4 revealed a pathologic homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype. CONCLUSIONS: A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.
BACKGROUND: Bilateral renal agenesis (BRA) is a lethal con genital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios on fetal ultrasonography reveals BRA. Although the exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics do not pick up many clinical patients. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development, and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia. METHODS: A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy, due to suspected BRA. Whole-exome sequencing (WES)-based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype. RESULTS: WES and evaluation of homozygous regions in II:3 and II:4 revealed a pathologic homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype. CONCLUSIONS: A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.
Authors: J G Pichel; L Shen; H Z Sheng; A C Granholm; J Drago; A Grinberg; E J Lee; S P Huang; M Saarma; B J Hoffer; H Sariola; H Westphal Journal: Nature Date: 1996-07-04 Impact factor: 49.962
Authors: M W Moore; R D Klein; I Fariñas; H Sauer; M Armanini; H Phillips; L F Reichardt; A M Ryan; K Carver-Moore; A Rosenthal Journal: Nature Date: 1996-07-04 Impact factor: 49.962
Authors: Michael A Skinner; Shawn D Safford; Justin G Reeves; Margaret E Jackson; Alex J Freemerman Journal: Am J Hum Genet Date: 2008-01-31 Impact factor: 11.025
Authors: Amelie T van der Ven; Birgit Kobbe; Stefan Kohl; Shirlee Shril; Hans-Martin Pogoda; Thomas Imhof; Hadas Ityel; Asaf Vivante; Jing Chen; Daw-Yang Hwang; Dervla M Connaughton; Nina Mann; Eugen Widmeier; Mary Taglienti; Johanna Magdalena Schmidt; Makiko Nakayama; Prabha Senguttuvan; Selvin Kumar; Velibor Tasic; Elijah O Kehinde; Shrikant M Mane; Richard P Lifton; Neveen Soliman; Weining Lu; Stuart B Bauer; Matthias Hammerschmidt; Raimund Wagener; Friedhelm Hildebrandt Journal: PLoS One Date: 2018-01-19 Impact factor: 3.240
Authors: Janina Müller-Deile; Nina Sopel; Alexandra Ohs; Victoria Rose; Marwin Gröner; Christoph Wrede; Jan Hegermann; Christoph Daniel; Kerstin Amann; Gunther Zahner; Mario Schiffer Journal: J Am Soc Nephrol Date: 2021-11 Impact factor: 10.121