A novel missense mutation in GREB1L identified in a three-generation family with renal hypodysplasia/aplasia-3

Abstract

Background Renal hypodysplasia/aplasia-3 (RHDA3), as the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract, is mainly caused by mutations in GREB1L. However, the mutations in GREB1L identified to date only explain a limited proportion of RHDA3 cases, and the mechanism of GREB1L mutations causing RHDA3 is unclear. Results According to whole-exome sequencing, a three-generation family suffering from RHDA3 was investigated with a novel missense mutation in GREB1L, c.4507C>T. All three-generation patients suffered from unilateral absent kidney. This missense mutation resulted in sharp downregulation of mRNA and protein expression, which might lead to RHDA3. Mechanistically, through RNA-sequencing, it was found that the mRNA levels of PAX2 and PTH1R, which are key molecules involved in the development of the kidney, were significantly downregulated by knocking out GREB1L in vitro. Conclusions This novel missense mutation in GREB1L can be helpful in the genetic diagnosis of RHDA3, and the discovery of the potential mechanism that GREB1L mutations involved in RHDA3 pathogenesis can promote the adoption of optimal treatment measures and the development of personalized medicine directly targeting these effects.

The genetic etiologies of bilateral renal agenesis

“…RDH types 1, 2, and 3 have been attributed to ITGA8 , FGF20 , and GREB1L , respectively. Renal Hypodysplasia/Aplasia 1 (RHDA1) is caused by homozygous or compound heterozygous mutations in ITGA8 (coding for integrin subunit alpha 8, critical in embryonic kidney development) or FGF20 17,62,105 . We previously discussed FGF20 and RHD2 in the section on BRA only.…”

“…GREB1L encodes for a protein likewise critical in the tubule development of the kidney, and in Wolffian and Mullerian duct formation. Associated with RDHA3, the most severe type of RDH, a heterozygous loss‐of‐function or missense variant in GREB1L can cause BRA, and mutations in this gene are also associated with other urogenital as well as skeletal, ear, and sometimes cardiac abnormalities 17,54,105 …”

“…Renal Hypodysplasia/Aplasia 1 (RHDA1) is caused by homozygous or compound heterozygous mutations in ITGA8 (coding for integrin subunit alpha 8, critical in embryonic kidney development) or FGF20. 17,62,105 We previously discussed in LPR4 exhibiting renal agenesis (BRA or URA) or renal hypoplasia. 68 Murine LPR4 knockout studies 108 have corroborated bilateral or URA.…”

“…GREB1L encodes for a protein likewise critical in the tubule development of the kidney, and in Wolffian and Mullerian duct formation. Associated with RDHA3, the most severe type of RDH, a heterozygous loss-of-function or missense variant in GREB1L can cause BRA, and mutations in this gene are also associated with other urogenital as well as skeletal, ear, and sometimes cardiac abnormalities 17,54,105. GLI3-related Pallister-Hall syndrome has a spectrum of abnormalities aside from BRA/URA: postaxial or mesoaxial polydactyly, bifid epiglottis, laryngotracheal cleft, anal atresia or stenosis and hypothalamic hamartoma and pituitary insufficiency.…”

Patient-derived podocyte spheroids reveal new insights into the etiopathogenesis of Alport syndrome

“…Moreover, our Q-PCR analysis showed that the point mutation in COL4A5 in the AS3 cell line was associated with a downregulation of this gene, and simultaneous upregulation of COL4A1 and LAMA1, supporting the idea that gene expression of the different collagen α chains is tightly controlled by quality check points. Moreover, the low expression of COL4A5 in the AS3 cell line may be due to excessive instability of the mutant mRNA (Roos and de Boer, 2021;Wu et al, 2022).…”