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Mutations in pseudohypoparathyroidism 1a and pseudopseudohypoparathyroidism in ethnic Chinese.
- Source :
-
PloS one [PLoS One] 2014 Mar 20; Vol. 9 (3), pp. e90640. Date of Electronic Publication: 2014 Mar 20 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- Subjects :
- Adolescent
Amino Acid Sequence
Animals
Base Sequence
COS Cells
Child
Child, Preschool
China
Chlorocebus aethiops
Chromogranins
Female
GTP-Binding Protein alpha Subunits, Gs chemistry
GTP-Binding Protein alpha Subunits, Gs genetics
Humans
Kidney diagnostic imaging
Leukocytes, Mononuclear metabolism
Male
Molecular Sequence Data
Radiography
Reverse Transcriptase Polymerase Chain Reaction
Ultrasonography
Urinary Bladder diagnostic imaging
Asian People genetics
Ethnicity genetics
Mutation genetics
Pseudohypoparathyroidism genetics
Pseudopseudohypoparathyroidism genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24651309
- Full Text :
- https://doi.org/10.1371/journal.pone.0090640