Endocrine Abstracts

The GNAS complex locus on chromosome 20q13.3 encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. With the exception of the transcriptional start site giving rise to Gsα, at least four GNAS regions undergo parent-specific epigenetic changes. Several human disorders are caused by mutations in GNAS or adjacent genomic regions. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 that lead to PTH-resistant hypocalcemia and hyperphosphatemia. Affected patients furthermore can present with resistance to TSH and other hormones, and typically develop characteristic abnormalities referred to as Albright’s Hereditary Osteodystrophy (AHO). The same or similar mutations on the paternal allele also cause some of these AHO features, but without mineral ion changes, and this disorder is therefore referred to as pseudopseudohypoparathyroidism (PPHP). Other heterozygous mutations on the maternal allele (including deletions, duplications, insertions, and inversions) lead to epigenetic changes at one or several GNAS DMRs (Differentially Methylated Regions), thereby causing autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). The genetic defect(s) responsible for sporadic PHP1B (sporPHP1B) remains unknown for most cases, yet characteristic epigenetic changes at the GNAS DMRs can be readily detected. Thus, multiple genetic or epigenetic GNAS abnormalities impair Gsα function thereby reducing cAMP-dependent signaling events down-stream of various G protein-coupled receptors.