ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P117

Simultaneous detection of a heterozygous deletion in the STX16 gene and loss of methylation at GNAS1A by methylation-specific MLPA in two patients with pseudohypoparathyroidism type 1b (PHP 1b)

Susanne Clausmeyer1, Gerd Perschon2, Anders Nygren3, Egbert Schulze1 & Friedhelm Raue1

1Endocrine Practice, Heidelberg, Germany; 2Practice for Internal Medicine and Nephrology, Bremerhaven, Germany; 3MRC-Holland, Amsterdam, The Netherlands.

The GNAS locus (chromosome 20q13) yields multiple transcripts, including the stimulatory G protein subunit α (Gsα), NESP55, GsαXL and two noncoding RNAs, the GNAS1A-transcript (A/B) and the antisense transcript (AS). The corresponding promoters show a complex methylation pattern resulting in an allele-specific imprinting, with maternal expression of NESP55 and paternal expression of GNAS1A, GsαXL and AS. Gsα in most tissues is derived from both alleles, except for the renal proximal tubules where it is exclusively maternally expressed. Expression of Gsα from the maternal allele in the kidney apparently requires silencing of GNAS1A by methylation, loss of methylation at GNAS1A leads to suppression of Gsα. Different endocrine disorders are associated with inactivating or activating mutations as well as impaired imprinting at the GNAS locus. Impaired imprinting of GNAS1A on the maternal allele has been identified as the underlying cause of PHP1b, a disease characterized by hypocalcemia, hyperphosphatemia and elevated serum levels of parathyroid hormone (PTH), due to renal resistance to PTH. We here describe two patients, sisters aged 30 and 33 years, respectively, who presented with hypocalcemia (1.69 and 1.7 mmol/l; normal range 2.2–2.65 mmol/l), hyperphosphatemia (1.54 and 1.68 mmol/l; normal range 0.87–1.45 mmol/l), and elevated PTH (378 pg/ml; normal range 10–65 pg/ml) but no other endocrine abnormalities. Sequencing of the Gsα gene did not reveal any mutations. By methylation-specific MLPA we detected a heterozygous deletion of exon 5 and 6 of the syntaxin-16 (STX16) gene and a loss of methylation at GNAS1A. A deletion within STX16, located about 220 kb upstream of GNAS1A, resulting in loss of methylation at GNAS1A, has been reported in multiple kindreds with PHP1b. Methylation-specific MLPA offers the possibility of detecting deletions as well as impaired methylation at the GNAS locus in a single assay.

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