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Link to original content: http://omim.org/entry/615721
ORPHA: 1848, 411709;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p22 | ?Renal hypodysplasia/aplasia 2 | 615721 | Autosomal recessive | 3 | FGF20 | 605558 |
A number sign (#) is used with this entry because of evidence that renal hypodysplasia/aplasia-2 (RHDA2) is caused by homozygous mutation in the FGF20 gene (605558) on chromosome 8p22. One such family has been reported.
Renal hypodysplasia/aplasia belongs to a group of perinatally lethal renal diseases, including bilateral renal aplasia, unilateral renal agenesis with contralateral dysplasia (URA/RD), and severe obstructive uropathy. Renal aplasia falls at the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT; 610805), and usually results in death in utero or in the perinatal period. Families have been documented in which bilateral renal agenesis or aplasia coexists with unilateral renal aplasia, renal dysplasia, or renal aplasia with renal dysplasia, suggesting that these conditions may belong to a pathogenic continuum or phenotypic spectrum (summary by Joss et al., 2003; Humbert et al., 2014).
For a discussion of genetic heterogeneity of renal hypodysplasia/aplasia, see RHDA1 (191830).
Barak et al. (2012) reported a highly consanguineous Caucasian family in which 2 pairs of sib fetuses related as first cousins had bilateral renal agenesis associated with anhydramnios. All the pregnancies were terminated. Postmortem examination of 1 affected fetus showed the Potter sequence, with redundant skin, varus feet, and pulmonary hypoplasia. Internal examination showed bilateral renoureteral agenesis; other organs were normal. Neuropathologic examination showed no brain or eye abnormalities.
The transmission pattern of RHDA2 in the family reported by Barak et al. (2012) was consistent with autosomal recessive inheritance.
In 3 affected fetuses from a consanguineous family with bilateral renal aplasia, Barak et al. (2012) identified a homozygous frameshift mutation in the FGF20 gene (605558.0002). The mutation, which was found using a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Loss of Fgf20 and Fgf9 (600921) in mice resulted in kidney agenesis, supporting the pathogenicity of the mutation in this family (see ANIMAL MODEL).
In the developing mouse kidney, Barak et al. (2012) demonstrated that Fgf9 and Fgf20 act as ligands for the niche signal required to maintain stem cells in the progenitor state. Studies of mutant mice with various combinations of loss of Fgf20 and Fgf9 showed that these 2 genes acted redundantly and were essential for kidney development. Reduction of Fgf20 and Fgf9 levels resulted in a reduction in kidney size and fewer glomeruli resulting from a smaller progenitor pool that differentiated normally. One wildtype Fgf20 allele in Fgf9-null embryos was enough to support normal kidney development, but Fgf20-null embryos with 1 wildtype Fgf9 allele had a more severe phenotype, suggesting that Fgf20 has a more dominant role than Fgf9 in the kidney. Fgf20-null kidneys with 1 wildtype Fgf9 allele were characterized by a loss of progenitor cells and the presence of premature differentiation of functional nephrons. Fgf20 was expressed exclusively within nephron progenitors, whereas Fgf9 was expressed mostly in the ureteric bud with signaling to the metanephric mesenchyme. In vitro studies indicated that Fgf20 or Fgf9, alone or together with Bmp7 (112267), maintained isolated metanephric mesenchyme and nephron progenitors that remained competent to differentiate.
Barak, H., Huh, S.-H., Chen, S., Jeanpierre, C., Martinovic, J., Parisot, M., Bole-Feysot, C., Nitschke, P., Salomon, R., Antignac, C., Ornitz, D. M., Kopan, R. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22: 1191-1207, 2012. [PubMed: 22698282] [Full Text: https://doi.org/10.1016/j.devcel.2012.04.018]
Humbert, C., Silbermann, F., Morar, B., Parisot, M., Zarhrate, M., Masson, C., Tores, F., Blanchet, P., Perez, M.-J., Petrov, Y., Khau Van Kien, P., Roume, J., and 9 others. Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans. Am. J. Hum. Genet. 94: 288-294, 2014. Note: Erratum: Am. J. Hum. Genet. 94: 799 only, 2014. [PubMed: 24439109] [Full Text: https://doi.org/10.1016/j.ajhg.2013.12.017]
Joss, S., Howatson, A., Trainer, A., Whiteford, M., FitzPatrick, D. R. De novo translocation (1;2)(q32;p25) associated with bilateral renal dysplasia. (Letter) Clin. Genet. 63: 239-240, 2003. [PubMed: 12694239] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00037.x]