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Identification by whole genome sequencing of a 140Kb inversion in GNAS locus involving NPELP1 and Xlas gene in a family presenting an autosomal dominant pseudohypoparathyroidism type 1b
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National audience. The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα) and additional imprinted transcripts. Pseudohypoparathyroidism type 1b (PHP1b) is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH), which occurs typically in the absence of any features of Albright's hereditary osteodystrophy. PHP1b is caused by epigenetic modifications at one or several differentially methylated regions (DMR) within GNAS locus that reduce transcription of Gsα from the maternal allele, resulting in diminished GSα expression in the tissues in which the paternal Gsα allele is normally silenced. The most frequent genetic cause for the autosomal dominant PHP1b (AD-PHP1b) is the maternally inherited STX16 deletion, which leads to isolated loss-of-methylation (LOM) at exon A/B alone. Other rare molecular mechanisms are described, especially copy numbers abnormalities encompassing one or several DMRs (NEPS55, NESPAS, XLas).
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