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Identification of a Novel GNAS Mutation in a Case Of Long et al. BMC Medical Genetics (2018) 19:132 https://doi.org/10.1186/s12881-018-0648-z RESEARCH ARTICLE Open Access Identification of a novel GNAS mutation in a case of pseudohypoparathyroidism type 1A with normocalcemia Xiao-dan Long1, Jing Xiong1, Zhao-hui Mo1, Chang-sheng Dong2 and Ping Jin1* Abstract Background: Pseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disease primarily characterized by resistance to parathyroid hormone along with hormonal resistance and other features of Albright hereditary osteodystrophy (AHO). It is caused by heterozygous inactivating mutations in the maternal allele of the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Herein, we report a case of of PHP1A with atypical clinical manifestations (oligomenorrhea, subclinical hypothyroidism, and normocalcemia) and explore the underlying genetic cause in this patient. Methods: Blood samples were collected from the patient, her family members, and 100 healthy controls. The 13 exons and flanking splice sites of the GNAS gene were amplified by PCR and sequenced. To further assess whether the novel mutation resulted in gain or loss of function of Gsα, we examined the level of cAMP activity associated with this mutation through in vitro functional studies by introducing the target mutation into a human GNAS plasmid. Results: A novel heterozygous c.715A > G (p.N239D) mutation in exon 9 of the GNAS gene was identified in the patient. This mutation was also found in her mother, who was diagnosed with pseudopseudohypoparathyroidism. An in vitro cAMP assay showed a significant decrease in PTH-induced cAMP production in cells transfected with the mutant plasmid, compared to that in the wild-type control cells (P < 0.01), which was consistent with loss of Gsa activity. Conclusion: We identified a novel GNAS mutation that altered Gsα function, which furthers our understanding of the pathogenesis of this disease. Screening for GNAS mutations should be considered in suspected cases of PHP1A even if the classical signs are not present. Keywords: Pseudohypoparathyroidism type 1A, GNAS gene, Stimulatory G-protein alpha subunit, Mutation Background (OMIM 612462) and PHP2 (OMIM 203330) [4, 5]. Pseudohypoparathyroidism (PHP) is a rare heterogeneous PHP1A and PHP1B are the most prevalent subtypes, with disease characterized by hypocalcemia and hyperphospha- similar prevalence rates (48% vs 46%) according to a temia due to resistance to parathyroid hormone (PTH) in recent study by Elli et al [6]. PHP1A is characterized by target organs [1]. Its prevalence is estimated to be 0.34/ target organ resistance to parathyroid hormone (PTH) and 100000 in Japan [2] and 1.1/100000 in Denmark [3]. PHP features of Albright’s Hereditary Osteodystrophy (AHO) is classified into different types based upon distinct bio- such as round face, short stature, subcutaneous calcifica- chemical profiles and clinical manifestations, including tions and brachydactyly, whereas PHP1B classically PHP1A(OMIM 103580), PHP1B (OMIM 603233), PHP1C presents as hormone resistance limited to PTH without AHO signs. PHP1A is caused by heterozygous inactivating * Correspondence: [email protected] 1 germline mutations in the guanine nucleotide-binding pro- Department of Endorcrinology, The third Xiangya Hospital Central South α GNAS University, Tongzipo Road, 410007 Changsha, Hunan Province, People’s tein -stimulating polypeptide ( ) gene located at Republic of China chromosome 20q13.3 [7]. PHP1A is inherited as an Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Long et al. BMC Medical Genetics (2018) 19:132 Page 2 of 7 autosomal-dominant trait under imprinting caused by gen- oligomenorrhea with only one to two menstrual periods etic alterations at the maternal allele. per year. Two years prior to presentation, she was diag- The protein encoded by the GNAS gene is the nosed with subclinical hypothyroidism with an elevated α-subunit of the stimulatory GTP binding protein (Gsα), thyroid-stimulating hormone (TSH) level of 16.1 μIU/mL which is involved in a large number of signal transduc- (reference range [RR], 0.5–4.3 μIU/mL) and a normal free tion pathways for multiple hormones via the stimulation thyroxine (FT4) level. L-thyroxine replacement treatment of adenylyl cyclase through production of cyclic AMP was started, but her TSH level remained high (10.7~ 26.09 (cAMP) [8]. To date, more than 400 inactivating GNAS μIU/mL) despite the use of increasing doses of mutations have been reported, including frameshift, L-thyroxine from 50 μgto200μ q.d. On physical examin- missense, nonsense, splice-site mutations, in-frame dele- ation, she showed features of AHO: round face, short stat- tions or insertions, and whole or partial gene deletions ure, obesity (body weight = 60 kg, height = 150 cm, body [6], and most of them lead to a truncated protein. These mass index = 26.7 kg/m2), brachymetatarsia (Fig. 2a,b)and mutations are scattered throughout the whole coding brachydactyly (Fig. 2c,d), without subcutaneous or intra- region of GNAS and only a recurring 4-bp deletion in cranial calcifications. Laboratory tests revealed elevated exon 7 (p.D190MfsX14) has been considered a mutational serum PTH, high-to-normal serum phosphate, normal hot spot [9]. In general, no genotype–phenotype correl- serum calcium, and 25-hydroxyvitamin D3 levels (Table 1). ation has been found for the inactivating GNAS muta- A low 24-h urinary calcium measurement of 0.83 mmol/ tions. However, a temperature-sensitive Gsα mutant day (RR, 2.5–7.5 mmol/day) was recorded, whereas renal (p.A366S) that causes testotoxicosis has been described in tubular reabsorption of phosphate (TmP/GFR) was previous studies [10, 11]. 1.05 mmol/L (RR, 0.81–1.45 mmol/L). Other investiga- Elevated levels of PTH and serum phosphate as well tions revealed that she had subclinical hypothyroidism as a low level of serum calcium are the hallmark features with a high serum TSH level and normal FT4 level and of PHP1A. Here, we report a novel heterozygous GNAS was negative for thyroid autoantibodies. Her serum mutation in a female patient who initially presented to follicle-stimulating hormone (FSH) and luteinizing us with oligomenorrhea and was subsequently diagnosed hormone (LH) levels were a slightly elevated, and her with PHP1A despite characteristics of normocalcemia estradiol level was low (Table 1), resembling hypergonado- and normophosphatemia. tropic hypogonadism. She had a normal basal cortisol level and increased adrenocorticotropic hormone (ACTH) Methods concentration (Table 1), but clinical signs of adrenal defi- Patients ciency were not observed. Her growth hormone (GH) We studied a family affected by PHP (Fig. 1). The pro- level, blood glucose level, and islet function were all nor- band was an 18-year-old girl who was referred to our mal (Table 1). Osteopenia of the lumbar spine with a Z hospital in 2016 because of 6 years of irregular menstru- score of − 1.5 was revealed on a bone mineral density test. ation and 2 years of thyroid dysfunction. She had first Based on these clinical and biochemical findings, she was menstruation at the age of 12 years, and thereafter had diagnosed with PHP1A. Subsequently, the patient was prescribed calcitriol (0.5 μg/bid), L-thyroxine (75 μg/q.d), and estrogen-progesterone combinations. On follow-up visits, her serum PTH level gradually decreased to 72.5– 94.7 pg/ml, her serum TSH level reached 6.6~ 8.4 μIU/ mL, and her 24-h urinary calcium was 1.8 mmol/day (RR, 2.5–7.5 mmol/day). No consanguinity was found for her parents. Her father showed normal appearance and average adult height (165 cm). Her mother was diagnosed with pseu- dopseudohypoparathyroidism (PPHP) and showed fea- tures of AHO, such as round face, short stature (140 cm), and slight brachymetatarsia (Fig. 2e,f), but no biochemical abnormalities (Table 1). Blood samples were collected from the patient, her family members, and 100 healthy Chinese controls (56 women and 44 men, age 36.1 ± 9.8 years). This study was approved by the Institutional Ethics Fig. 1 Pedigree of the studied family; the proband is indicated by Committee of The Third Xiangya Hospital. Written in- the arrow formed consent was obtained from all subjects enrolled Long et al. BMC Medical Genetics (2018) 19:132 Page 3 of 7 Fig. 2 (a) Photograph of the patients feet and (b) X-ray of the left feet showing brachymetatarsia. (c) Photograph of the patient’s hands and (d) X-ray of her hands (d) showing brachydactyly, typical of Albright’s osteodystrophy. (e) Photograph of the patient’s mothers hand and (f) X-ray of her hands (f) also showing slight brachydactyly similar to her daughter in this study, who agreed to join this study, with the in- Mutations were identified by direct sequencing of PCR tent of using the medical data for scientific research and products on an ABI 3730xl automated sequencer (Ap- publication. plied Biosystems, USA). Mutation analysis Cell transfection and stimulation Genomic DNA was extracted from peripheral blood leu- To determine the phenotypic effects of the genetic muta- kocytes by standard phenol–chloroform procedures. All tion, we performed site-directed mutagenesis in an in vitro 13 exons and adjacent exon–intron sequences of the assay.
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