title: Mutations in pseudohypoparathyroidism 1a and pseudopseudohypoparathyroidism in ethnic Chinese.
abstract: An inactivating mutation in the GNAS gene causes either pseudohypoparathyroidism 1a (PHP1A) when it is maternally inherited or pseudopseudohypoparathyroidism (PPHP) when it is paternally inherited. We investigated clinical manifestations and mutations of the GNAS gene in ethnic Chinese patients with PHP1A or PPHP. Seven patients from 5 families including 4 girls and 2 boys with PHP1A and 1 girl with PPHP were studied. All PHP1A patients had mental retardation. They were treated with calcitriol and CaCO3 with regular monitoring of serum Ca levels, urinary Ca/Cr ratios, and renal sonography. Among them, 5 patients also had primary hypothyroidism suggesting TSH resistance. One female patient had a renal stone which was treated with extracorporeal shockwave lithotripsy. She had an increased urinary Ca/Cr ratio of 0.481 mg/mg when the stone was detected. We detected mutations using PCR and sequencing as well as analysed a splice acceptor site mutation using RT-PCR, sequencing, and minigene construct. We detected 5 mutations: c.85C>T (Q29*), c.103C>T (Q35*), c.840-2A>G (R280Sfs*21), c.1027_1028delGA (D343*), and c.1174G>A (E392K). Mutations c.840-2A>G and c.1027_1028delGA were novel. The c.840-2A>G mutation at the splice acceptor site of intron 10 caused retention of intron 10 in the minigene construct but skipping of exon 11 in the peripheral blood cells. The latter was the most probable mechanism which caused a frameshift, changing Arg to Ser at residue 280 and invoking a premature termination of translation at codon 300 (R280Sfs*21). Five GNAS mutations in ethnic Chinese with PHP1A and PPHP were reported. Two of them were novel. Mutation c.840-2A>G destroyed a spice acceptor site and caused exon skipping. Regular monitoring and adjustment in therapy are mandatory to achieve optimal therapeutic effects and avoid nephrolithiasis in patients with PHP1A.
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan; Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Yi-Lei
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Daw-Yang
authors.initials: DY
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, Kaohsiung Municipal Hsiao Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hui-Pin
authors.initials: HP
authors.lastname: Hsiao
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan.
authors.forename: Wei-Hsin
authors.initials: WH
authors.lastname: Ting
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Tsai
authors.affiliation: Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Renal Care, Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hung-Chun
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Division of Genetics, Endocrinology and Metabolism, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Mei-Chyn
authors.initials: MC
authors.lastname: Chao
authors.affiliation: Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Fu-Sung
authors.initials: FS
authors.lastname: Lo
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan; College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jeng-Daw
authors.initials: JD
authors.lastname: Tsai
authors.affiliation: Department of Urology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Stone
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Radiology, Mackay Memorial Hospital, Taipei, Taiwan; College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shin-Lin
authors.initials: SL
authors.lastname: Shih
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan; Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan; Department of Infant and Child Care, National Taipei University of Nursing and Health, Taipei, Taiwan; Institute of Biomedical Sciences and Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Shuan-Pei
authors.initials: SP
authors.lastname: Lin
authors.affiliation: Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chiung-Ling
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan; Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan; College of Medicine, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Yann-Jinn
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002681:China; D002522:Chlorocebus aethiops; D002864:Chromogranins; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000000981:diagnostic imaging; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D011556:Pseudopseudohypoparathyroidism / Q000235:genetics*; D011859:Radiography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014463:Ultrasonography; D001743:Urinary Bladder / Q000000981:diagnostic imaging
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs