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Human Molecular Genetics, 2001, Vol. 10, No. 12 1231-1241
© 2001 Oxford University Press

Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus

M. Bastepe, J. E. Pincus, T. Sugimoto2, K. Tojo3, M. Kanatani2, Y. Azuma4, K. Kruse5, A. L. Rosenbloom6, H. Koshiyama7 and H. Jüppner1,+

Endocrine Unit, Massachusetts General Hospital and 1MassGeneral Hospital for Children, and Harvard Medical School, Boston, MA, USA, 2Third Division, Department of Medicine, Kobe University School of Medicine, Kobe, Japan, 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Tokyo Jikei University School of Medicine, Tokyo, Japan, 4Department of Internal Medicine, Kyoto National Hospital, Kyoto, Japan, 5Universitätsklinikum, Klinik für Kinder- und Jugendmedizin, Lübeck, Germany, 6University of Florida, Department of Pediatrics, Division of Endocrinology, Gainesville, FL, USA, 7Division of Endocrinology and Metabolism, Department of Internal Medicine, Hyogo Prefectural Amagasaki Hospital, Hyogo, Japan

Pseudohypoparathyroidism type Ib (PHP-Ib) is a paternally imprinted disorder which maps to a region on chromosome 20q13.3 that comprises GNAS1 at its telomeric boundary. Exon A/B of this gene was recently shown to display a loss of methylation in several PHP-Ib patients. In nine unrelated PHP-Ib kindreds, in whom haplotype analysis and mode of inheritance provided no evidence against linkage to this chromosomal region, we confirmed lack of exon A/B methylation for affected individuals, while unaffected carriers showed no epigenetic abnormality at this locus. However, affected individuals in one kindred (Y2) displayed additional methylation defects involving exons NESP55, AS and XL, and unaffected carriers in this family showed an abnormal methylation at exon NESP55, but not at other exons. Taken together, current evidence thus suggests that distinct mutations within or close to GNAS1 can lead to PHP-Ib and the associated epigenetic changes. To further delineate the telomeric boundary of the PHP-Ib locus, the previously reported kindred F, in which patient F-V/51 is recombinant within GNAS1, was investigated with several new markers and direct nucleotide sequence analysis. These studies revealed that F-V/51 remains recombinant at a single nucleotide polymorphism (SNP) located 1.2 kb upstream of XL. No heterozygous mutation was identified between exon XL and an SNP ~8 kb upstream of NESP55, where this affected individual becomes linked, suggesting that the genetic defect responsible for parathyroid hormone resistance in kindred F, and probably other PHP-Ib patients, is located >=56 kb centromeric of the abnormally methylated exon A/B. A region upstream of the known coding exons of GNAS1 is therefore predicted to exert, presumably through imprinting of exon A/B, long-range effects on Gs{alpha} expression.

+ To whom correspondence should be addressed at: Endocrine Unit, Wellman 5, Massachusetts General Hospital, Boston, MA 02114, USA; Tel: +1 617 726 3966; Fax: +1 617 726 7543; Email: jueppner@helix.mgh.harvard.edu


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