Identification of a novel GNAS mutation in a case of pseudohypoparathyroidism type 1A with normocalcemia

Abstract

BackgroundPseudohypoparathyroidism 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.MethodsBlood 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.ResultsA 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0648-z) contains supplementary material, which is available to authorized users.

GNAS mutation is an unusual cause of primary adrenal insufficiency: a case report

“…Ridderskamp et al [ 15 ] believe that PHP patients can be accompanied by ACTH resistance, as they detected hypocortisolism in an adult PHP case. This opinion was supported by three other reports which found elevated ACTH levels or an exaggerated ACTH response to CRH in PHP patients [ 16 – 18 ]. Chaubey et al [ 19 ] also reported a case of GNAS mutation with primary adrenal insufficiency, although the author believes that the adrenal insufficiency was idiopathic.…”

Central Precocious Puberty in a Boy with Pseudohypoparathyroidism Type 1A due to a Novel GNAS Variant, with Congenital Hypothyroidism as the First Manifestation

“…Delayed or incomplete puberty with elevated gonadotropin levels could thus be one of the PHP1A phenotypes. Symptomatic gonadotropin resistance has been detected more commonly in female PHP1A patients while elevation of gonadotropin levels without symptoms has rarely been reported in male PHP1A patients ( 2 , 3 , 8 , 9 , 10 , 11 , 12 ). Interestingly, our patient developed CPP instead, which is exceptionally rare among patients with PHP1A.…”

“…Some PHP1A patients also demonstrate elevated gonadotropin levels which represents gonadotropin resistance ( 8 , 9 , 10 , 11 , 12 ). This finding was mainly reported in female PHP1A patients who presented with either amenorrhea or oligomenorrhea ( 9 , 10 , 11 ). In contrast, male PHP1A patients were rarely reported to have gonadotropin resistance ( 10 , 11 , 12 ).…”

Pseudohypoparathyroidism Type 1A with Normocalcaemia, due to the Novel C.389A&gt;G Variant of Exon 5 of the Guanine Nucleotide-Binding Protein, α-Stimulating Gene

“…[8] Our patient, with his novel molecular profile, represents one of these cases of slow progression, where mild PTH resistance is accompanied by normocalcaemia until the age of our follow-up, similar to several other cases. [9][10][11][12] The genetic cause of PHP1A lies on a locus with imprint-ing phenomenon, which is explained by the tissue-specific monoallelic expression of different parental alleles of Gsα. [13] To date, there are more than 340 different GNAS mutations, which are causative of PHP1A.…”

“…[ 8 ] Our patient, with his novel molecular profile, represents one of these cases of slow progression, where mild PTH resistance is accompanied by normocalcaemia until the age of our follow-up, similar to several other cases. [ 9 – 12 ]…”