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
Affiliations
Yasuhisa Ohata
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
Haruna Kakimoto
Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Yuko Seki
Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
Yasuki Ishihara
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; The first Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Japan; Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan
Yukako Nakano
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
Kenichi Yamamoto
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
Shinji Takeyari
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
Makoto Fujiwara
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; The first Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Japan
Taichi Kitaoka
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
Satoshi Takakuwa
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Pediatrics, Hyogo Prefectural Nishinomiya Hospital, Japan
Takuo Kubota
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
Keiichi Ozono
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; Corresponding author at: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
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.
