A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance.
BACKGROUND
Pseudohypoparathyroidism (PHP) type Ia is a rare maternally transmitted disease due to maternal loss-of-function mutations of GNAS, the gene encoding Galphas, the alpha-stimulatory subunit of the G protein. Affected individuals display hormonal resistance (mainly PTH and TSH resistance) and Albright hereditary osteodystrophy. PHP type Ib (PHP-Ib), usually defined by isolated renal resistance to PTH and sometimes mild TSH resistance, is due to a maternal loss of GNAS exon A/B methylation, leading to decreased Galphas expression in specific tissues.


OBJECTIVE
We report a girl with obvious Albright osteodystrophy features, PTH resistance, normal Galphas bioactivity in red blood cells, yet no loss-of-function mutation in the GNAS coding sequence (exons 1-13). The methylation analysis of the four GNAS differentially methylated regions, i.e. NESP, AS, XL, and A/B, revealed broad methylation changes at all differentially methylated regions, including GNAS exon A/B, leading to a paternal epigenotype on both alleles.


CONCLUSIONS
This observation suggests that: 1) the decreased expression of Galphas due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone; 2) PHP-Ib is a heterogeneous disorder that should lead to studying GNAS epigenotype in patients with PHP and no mutation in GNAS exons 1-13, regardless of their physical features.
Mariot
Virginie
V
Pediatric Endocrinology and Institut National de la Santé et de la Recherche Médicale U561, Hôpital St-Vincent de Paul, 82 avenue Denfert-Rochereau, 75014 Paris V University, France.
Maupetit-Méhouas
Stéphanie
S
Sinding
Christiane
C
Kottler
Marie-Laure
ML
Linglart
Agnès
A
D002648:Child; D002864:Chromogranins; D044127:Epigenesis, Genetic; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010281:Parathyroid Hormone / Q000502:physiology*; D011547:Pseudohypoparathyroidism / Q000235:genetics*
D002864:Chromogranins; C470125:PTH protein, human; D010281:Parathyroid Hormone; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs