Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis.
BACKGROUND
GNAS encodes the alpha-subunit of the stimulatory G protein as well as additional imprinted transcripts including the maternally expressed NESP55 and the paternally expressed XLalphas, antisense, and A/B transcripts. Most patients with pseudohypoparathyroidism type Ib (PHP-Ib) exhibit imprinting defects affecting the maternal GNAS allele, which are thought to reduce/abolish Gsalpha expression in renal proximal tubules and thereby cause resistance to PTH.


OBJECTIVE
Our objective was to define the genetic defect in a previously unreported family with autosomal dominant PHP-Ib.


METHODS
Analyses of serum and urine chemistries and of genomic DNA and lymphoblastoid-derived RNA were conducted at a tertiary hospital and research laboratory.


METHODS
Affected individuals presented with muscle weakness and/or paresthesia and showed hypocalcemia, hyperphosphatemia, and elevated serum PTH. Obligate carriers were healthy and revealed no obvious abnormality in mineral ion homeostasis.


RESULTS
A novel 4.2-kb microdeletion was discovered in the affected individuals and the obligate carriers, ablating two noncoding GNAS antisense exons while preserving the NESP55 exon. On maternal transmission, the deletion causes loss of all maternal GNAS imprints, partial gain of NESP55 methylation, and PTH resistance. Paternal transmission of the mutation leads to epigenetic alterations in cis, including a partial loss of NESP55 methylation and a partial gain of A/B methylation.


CONCLUSIONS
The identified deletion points to a unique cis-acting element located telomeric of the NESP55 exon that is critical for imprinting both GNAS alleles. These findings provide novel insights into the molecular mechanisms underlying PHP and GNAS imprinting.
Chillambhi
Smitha
S
Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street Thier 10, Boston, Massachusetts 02114, USA.
Turan
Serap
S
Hwang
Daw-Yang
DY
Chen
Hung-Chun
HC
Jüppner
Harald
H
Bastepe
Murat
M
D000328:Adult; D000704:Analysis of Variance; D015139:Blotting, Southern; D002864:Chromogranins; D019175:DNA Methylation; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D050031:Hashimoto Disease / Q000150:complications / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D011547:Pseudohypoparathyroidism / Q000150:complications / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion
D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
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