Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy

Gene: GNAS-AS1

Red List (low evidence)

Single report of a AD-PHP-Ib kindred with a maternally inherited deletion limited to GNAS-AS1 (Chillambhi et al 2010). Further reports of maternally inherited deletions including regions of both GNAS-AS1 and exon NESP55. Although deletions in this region appear to be causative of AD-PHP-Ib, evidence for deletions limited to only GNAS-AS1 is limited to date.

Note, this non-coding RNA is paternally expressed, but causative deletions have been maternally inherited.

Reports of two AD-PHP-Ib kindreds with 4-kb microdeletions comprising the entire NESP55 DMR. These include exon NESP55 (GNAS encoded) and exons 3 and 4 of the GNAS antisense transcript. It remains unknown whether the observed imprinting changes and PTH resistance in these patients result from the loss of NESP55 expression or the loss of the deleted genomic region.

Chillambhi et al reported a AD-PHP-Ib kindred and identified a novel deletion that exclusively affects exons encoding the GNAS-AS. Overlapping with the previously identified deletions by approximately 1.5 kb. Unlike the previously identified deletions associated with AD-PHP-Ib, the novel deletion not only disrupts methylation of three GNAS DMRs (A/B, AS, and XL) after maternal transmission but also appears to partially alter methylation of the NESP55 and the A/B DMRs after paternal transmission, revealing a novel cis-acting mechanism that governs imprinting on both parental alleles.

Rezwan et al reported two further families with 33bp and 40bp deletions intronic to both NESP55 and NESP-AS. These were not definitively causative of the phenotype in the family.

Created: 24 Oct 2021, 5:29 a.m. | Last Modified: 24 Oct 2021, 5:29 a.m.

Panel Version: 0.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)

Phenotypes
Pseudohypoparathyroidism type 1b MIM no: 603233

Publications

• 22378814
• 15592469
• 29959430
• 25005734