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Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism
Author(s) -
Jin Hye Young,
Lee Beom Hee,
Choi JinHo,
Kim GuHwan,
Kim JinKyung,
Lee Jung Hyun,
Yu Jeesuk,
Yoo JaeHo,
Ko Cheol Woo,
Lim HanHyuk,
Chung Hye Rim,
Yoo HanWook
Publication year - 2011
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2011.04026.x
Subject(s) - gnas complex locus , pseudohypoparathyroidism , multiplex ligation dependent probe amplification , exon , medicine , endocrinology , macrocephaly , methylation , dna methylation , genetics , biology , gene , parathyroid hormone , gene expression , calcium
Summary Objective Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations in the GNAS locus. Design Investigation of clinical characteristics and molecular analysis in PHP and PPHP. Patients Fourteen subjects from 13 unrelated families including subjects with PPHP ( n = 1), PHP‐Ia ( n = 6) and PHP‐Ib ( n = 7) were enrolled. Measurements Clinical data, including age at presentation, presenting symptom, auxological findings, family history, presence of Albright hereditary osteodystrophy (AHO) features and hormonal and biochemical findings, were analysed. The GNAS locus was subjected to direct sequencing and methylation analysis using methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA). Results Of the 13 PHP subjects, 10 (three PHP‐Ia and seven PHP‐Ib) presented with hypocalcemic tetany at ages ranging from 7 to 14·8 years. Subcutaneous calcification was observed as an early manifestation of AHO in one PHP‐Ia patient (age, 2·9 years) and one PPHP patient (age, 7 months). Six PHP‐Ia and one PPHP harboured four different heterozygous mutations within the coding region of GNAS, p.Asp189_Tyr190delinsMetfxX14, p.Val117fsX23, p.Tyr190CysfsX19, and a splicing mutation (c.659 + 1G>A), of which the latter two were novel. Five subjects with PHP‐Ib exhibited complete loss of the maternal‐specific methylation pattern. The remaining two PHP‐Ib showed a loss of methylation of exon 1A on the maternal allele as a consequence of heterozygous 3‐kb microdeletions within the STX16 gene. Conclusions GNAS mutation analyses and MS‐MLPA assays are useful molecular tools for understanding the molecular bases and confirming the diagnosis of PHP and PPHP.