Pathogenic variants of the GNAS gene introduce an abnormal amino acid sequence in the β6 strand/α5 helix of Gsα, causing pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism in two unrelated Japanese families

Yasuhisa Ohata; Haruna Kakimoto; Yuko Seki; Yasuki Ishihara; Yukako Nakano; Kenichi Yamamoto; Shinji Takeyari; Makoto Fujiwara; Taichi Kitaoka; Satoshi Takakuwa; Takuo Kubota; Keiichi Ozono

doi:10.1016/j.bonr.2022.101637

Pathogenic variants of the GNAS gene introduce an abnormal amino acid sequence in the β6 strand/α5 helix of Gsα, causing pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism in two unrelated Japanese families

Bone Rep. 2022 Nov 10:17:101637. doi: 10.1016/j.bonr.2022.101637. eCollection 2022 Dec.

Authors

Yasuhisa Ohata¹, Haruna Kakimoto², Yuko Seki², Yasuki Ishihara^{1

3

4}, Yukako Nakano¹, Kenichi Yamamoto^{1

5}, Shinji Takeyari¹, Makoto Fujiwara^{1

3}, Taichi Kitaoka¹, Satoshi Takakuwa^{1

6}, Takuo Kubota¹, Keiichi Ozono¹

Affiliations

¹ Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
² Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
³ The first Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Japan.
⁴ Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
⁶ Department of Pediatrics, Hyogo Prefectural Nishinomiya Hospital, Japan.

Abstract

Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of GNAS, which encodes Gsα. We present two unrelated Japanese families with PHP1A and PPHP harboring unreported pathogenic variants of GNAS (c.1141delG, p.Asp381Thrfs*23 and c.1117delC, p.Arg373Alafs*31). These variants introduce abnormal amino acids in the β6 strand/α5 helix of Gsα, which interact with G protein coupling receptor (GPCR). We conclude that these variants alter the association of Gsα with GPCR and cause PHP1A or PPHP.

Keywords: AHO, Albright's hereditary osteodystrophy; GNAS gene; GPCR, G protein coupling receptors;; Gsα; HGMD, Human Gene Mutation Database; IRB, Institutional review Board; NMD, Nonsense-mediated decay; Pseudohypoparathyroidism 1A (PHP1A); Pseudopseudohypoparathyroidism (PPHP); TSH, Thyroid-stimulating hormone; β6 strand/α5 helix.

Publication types

Case Reports