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.