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A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B).

Authors :
Grigelioniene, Giedre
Nevalainen, Pasi I
Reyes, Monica
Thiele, Susanne
Tafaj, Olta
Molinaro, Angelo
Takatani, Rieko
Ala-Houhala, Marja
Nilsson, Daniel
Eisfeldt, Jesper
Lindstrand, Anna
Kottler, Marie-Laure
Mäkitie, Outi
Jüppner, Harald
Source :
Journal of Bone & Mineral Research; Apr2017, Vol. 32 Issue 4, p776-783, 8p
Publication Year :
2017

Abstract

ABSTRACT Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most cases without evidence for Albright hereditary osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially-methylated regions (DMRs) within GNAS, which encodes the α-subunit of the stimulatory G protein (Gsα) and splice variants thereof. Heterozygous, maternally inherited STX16 or GNAS deletions leading to isolated loss-of-methylation (LOM) at exon A/B alone or at all maternal DMRs are the cause of autosomal dominant PHP1B (AD-PHP1B). In this study, we analyzed three affected individuals, the female proband and her two sons. All three revealed isolated LOM at GNAS exon A/B, whereas the proband's healthy maternal grandmother and uncle showed normal methylation at this locus. Haplotype analysis was consistent with linkage to the STX16/ GNAS region, yet no deletion could be identified. Whole-genome sequencing of one of the patients revealed a large heterozygous inversion (1,882,433 bp). The centromeric breakpoint of the inversion is located 7,225 bp downstream of GNAS exon XL, but its DMR showed no methylation abnormality, raising the possibility that the inversion disrupts a regulatory element required only for establishing or maintaining exon A/B methylation. Because our three patients presented phenotypes consistent with PHP1B, and not with PHP1A, the Gsα promoter is probably unaffected by the inversion. Our findings expand the spectrum of genetic mutations that lead to LOM at exon A/B alone and thus biallelic expression of the transcript derived from this alternative first GNAS exon. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
08840431
Volume :
32
Issue :
4
Database :
Complementary Index
Journal :
Journal of Bone & Mineral Research
Publication Type :
Academic Journal
Accession number :
122560779
Full Text :
https://doi.org/10.1002/jbmr.3083