ESPE Abstracts (2019) 92 FC3.1

ESPE2019 Free Communications Multi-system Endocrine Disorders (6 abstracts)

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

Maki Fukami 1 , Mami Miyado 1 , Shuji Takada 1 , Goro Sasaki 2 , Keisuke Nagasaki 3 , Youhei Masunaga 4 , Hirotomo Saitsu 4 & Tsutomu Ogata 4

1National Research Institute for Child Health and Development, Tokyo, Japan. 2Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan. 3Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 4Hamamatsu University School of Medicine, Hamamatsu, Japan

Background: The stimulatory G-protein α-subunit encoded by GNAS exons 1–13 (GNAS-Gsα) mediates signal transductions of multiple G-protein-coupled receptors including arginine vasopressin (AVP) receptor 2 (AVPR2). To date, various germline-derived loss-of-function variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism respectively, and specific somatic gain-of-function (GOF) variants have been detected in McCune-Albright syndrome (MAS). However, no germline-derived GOF variant has been identified.

Methods: We performed whole exome sequencing (WES) in family-A and family-B with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD), after excluding a GOF variant of AVPR2. We subsequently performed functional studies for identified variants.

Results: WES revealed p.(F68_G70del) and p.(M255V) of GNAS-Gsα as the candidate variants for NSIAD in family-A and family-B, respectively. Both variants were absent from public and in-house databases and, of genes with rare variants, GNAS-Gsα alone was involved in AVPR2-signaling and shared by the two families. Protein structural analyses revealed a GOF-compatible conformational property for p.M255V-Gsα, although such assessment was not possible for p.F68_G70del-Gsα. Luciferase reporter assays showed that both variants had constitutive activation functions which were significantly milder than those of MAS-specific Gsα variants. Model mice for p.F68_G70del-Gsα showed normal survivability and NSIAD-compatible phenotype, while those for p.M255V-Gsα exhibited severe failure to thrive. NSIAD was the sole clinically recognizable phenotype in the two families, while detailed clinical and laboratory studies in the GNAS-Gsα variant-positive subjects revealed subclinical hyperthyroidism in four subjects and hypocalciuria in a single subject.

Conclusions: This study shows for the first time that germline-derived GOF variants of GNAS-Gsα do exist and cause NSIAD as a novel Gsα-mediated genetic disease. It is likely that AVPR2-signaling is most sensitive to the GOF effects of GNAS-Gsα.

Volume 92

58th Annual ESPE

Vienna, Austria
19 Sep 2019 - 21 Sep 2019

European Society for Paediatric Endocrinology 

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