Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism.

Hye Young Jin, Beom Hee Lee, Jin-Ho Choi, Gu-Hwan Kim, Jin-Kyung Kim, Jung Hyun Lee, Jeesuk Yu, Jae-Ho Yoo, Cheol Woo Ko, Han-Hyuk Lim, Hye Rim Chung, Han-Wook Yoo

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Clinical endocrinology 2011 Aug

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Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations in the GNAS locus. Investigation of clinical characteristics and molecular analysis in PHP and PPHP. Fourteen subjects from 13 unrelated families including subjects with PPHP (n = 1), PHP-Ia (n = 6) and PHP-Ib (n = 7) were enrolled. 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). 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. GNAS mutation analyses and MS-MLPA assays are useful molecular tools for understanding the molecular bases and confirming the diagnosis of PHP and PPHP. © 2011 Blackwell Publishing Ltd.

Citation

Hye Young Jin, Beom Hee Lee, Jin-Ho Choi, Gu-Hwan Kim, Jin-Kyung Kim, Jung Hyun Lee, Jeesuk Yu, Jae-Ho Yoo, Cheol Woo Ko, Han-Hyuk Lim, Hye Rim Chung, Han-Wook Yoo. Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism. Clinical endocrinology. 2011 Aug;75(2):207-13