Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis

Abstract

BackgroundThe stimulatory G-protein α-subunit encoded by GNAS exons 1–13 (GNAS-Gsα) mediates signal transduction of multiple G protein–coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsα variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gsα variants have been detected in McCune–Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality.MethodsWe performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants.ResultsWhole-exome sequencing revealed two GNAS-Gsα candidate variants for NSIAD: GNAS-Gsα p.(F68_G70del) in one family and GNAS-Gsα p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsα alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function–compatible conformational property for p.M255V-Gsα, although such assessment was not possible for p.F68_G70del-Gsα. Both variants had gain-of-function effects that were significantly milder than those of McCune–Albright syndrome–specific somatic Gsα variants. Model mice for p.F68_G70del-Gsα showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsα exhibited severe failure to thrive.ConclusionsThis study shows that germline-derived gain-of-function rare variants of GNAS-Gsα exist and cause NSIAD as a novel Gsα-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsα’s gain-of-function effects.

Inherited Tubulopathies of the Kidney

“…Yet, no corresponding gain-of-function mutations in AQP2 have so far been described. Instead, mutations in GNAS have been identified as another cause of nephrogenic syndrome of inappropriate antidiuresis, either isolated or as part of a more complex syndrome, which reflects the association of GNAS with several G protein-coupled receptors (25,26). GNAS encodes the stimulatory G-a protein, which links AVPR2 activation to adenyl cyclase in the AVP signaling pathway (Figure 2) (27).…”

“…Why some GNAS mutations lead to syndromic features and others seem to cause isolated nephrogenic syndrome of inappropriate antidiuresis is currently unclear. It has been speculated that AVPR2 signaling may be the most sensitive GNAS-associated pathway, so that milder mutation manifest clinically only in impaired urinary dilution (25).…”

Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia

“…Captured libraries were sequenced by NextSeq 500 (Illumina) with 150 bp paired-end reads. Exome data processing, variant calling, and variant annotation were carried out, as described previously [ 27 ]. Human GRCh37 was utilized as the reference genome, and the PER2 variant was described according to the HGVS recommendations [ 28 ], using NM_022817.2 as the reference sequence ( https://www.ncbi.nlm.nih.gov/genbank ).…”

Primary ovarian insufficiency in a female with phosphomannomutase-2 gene (<i>PMM2</i>) mutations for congenital disorder of glycosylation

“…This study was approved by the Institutional Review Board Committee at Hamamatsu University School of Medicine, and was performed using leukocyte genomic DNA samples of the patient and the parents after obtaining written informed consent. WES was carried out by the previously described methods [7], using Human GRCh37/h19 as the reference genome. In short, WES was performed with SureSelect Human All Exon V6 (Agilent Technologies), and captured libraries were sequenced by NextSeq 500 (Illumina) with 150 bp paired-end reads.…”