Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.
Patients with pseudohypoparathyroidism type Ib (PHP-Ib) have hypocalcemia and hyperphosphatemia due to renal parathyroid hormone (PTH) resistance, but lack physical features of Albright hereditary osteodystrophy. PHP-Ib is thus distinct from PHP-Ia, which is caused by mutations in the GNAS exons encoding the G protein alpha subunit. However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS. Furthermore, loss of methylation at a differentially methylated region (DMR) of this locus, exon A/B, has been observed thus far in all investigated sporadic PHP-Ib cases and the affected members of multiple AD-PHP-Ib kindreds. We now report that affected members and obligate gene carriers of 12 unrelated AD-PHP-Ib kindreds and four apparently sporadic PHP-Ib patients, but not healthy controls, have a heterozygous approximately 3-kb microdeletion located approximately 220 kb centromeric of GNAS exon A/B. The deleted region, which is flanked by two direct repeats, includes three exons of STX16, the gene encoding syntaxin-16, for which no evidence of imprinting could be found. Affected individuals carrying the microdeletion show loss of exon A/B methylation but no epigenetic abnormalities at other GNAS DMRs. We therefore postulate that this microdeletion disrupts a putative cis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib.
Bastepe
Murat
M
Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Fröhlich
Leopold F
LF
Hendy
Geoffrey N
GN
Indridason
Olafur S
OS
Josse
Robert G
RG
Koshiyama
Hiroyuki
H
Körkkö
Jarmo
J
Nakamoto
Jon M
JM
Rosenbloom
Arlan L
AL
Slyper
Arnold H
AH
Sugimoto
Toshitsugu
T
Tsatsoulis
Agathocles
A
Crawford
John D
JD
Jüppner
Harald
H
D000293:Adolescent; D000328:Adult; D002648:Child; D002864:Chromogranins; D019175:DNA Methylation; D005091:Exons; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D017353:Gene Deletion; D018392:Genomic Imprinting; D006801:Humans; D010375:Pedigree; D011547:Pseudohypoparathyroidism / Q000235:genetics*
D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs