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.
Highlights
Albright hereditary osteodystrophy (AHO; OMIM #103580) was described by Albright and Smith in 1942 [1]
On the basis of the presence or absence of AHO, urinary cyclic adenosine monophosphate (cAMP) response to Parathyroid hormone (PTH) infusion, resistance to other peptide hormones, and diminished in vitro Gsa activity, PHP is categorized into pseudohypoparathyroidism 1a (PHP1A; OMIM #103580), pseudohypoparathyroidism 1b (PHP1B; OMIM #603233), pseudohypoparathyroidism 1c (PHP1C; OMIM #612462), and pseudohypoparathyroidism 2 (PHP2; OMIM %203330) [3,4,5]
Inactivating GNAS mutations on either the paternal or maternal allele result in Gsa deficiency leading to AHO [7] but resistance of target organs to PTH and other hormones which act through cAMP only if the mutations are on the maternal allele [8]
Summary
Albright hereditary osteodystrophy (AHO; OMIM #103580) was described by Albright and Smith in 1942 [1]. It is characterized by short stature, round facies, brachydactyly, and short fourth and fifth metacarpals, metatarsals, or both. Inactivating GNAS mutations on either the paternal or maternal allele result in Gsa deficiency leading to AHO [7] but resistance of target organs to PTH and other hormones which act through cAMP only if the mutations are on the maternal allele [8]. Four additional imprinted gene products from the GNAS complex locus are paternally expressed XLas, A/B ( referred as 1A) and antisense transcripts (GNASAS), and maternally expressed NESP55 transcript [9,10,11]
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