TY - JOUR
T1 - Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1
AU - De Beur, Suzanne Jan
AU - Ding, Changlin
AU - Germain-Lee, Emily
AU - Cho, Justin
AU - Maret, Alexander
AU - Levine, Michael A.
N1 - Funding Information:
We are grateful to Professor D. T. Bonthron, of Leeds, for providing a genomic GNAS1. This work was supported in part by United States Public Health Service Grants R01-DK34281, R01-DK46720, and T32-DK07751 (all to M.A.L.), and by the Johns Hopkins University School of Medicine General Clinical Research Center, National Institutes of Health/National Center for Research Resources grant M01 RR00052. S.J.d.B. was supported in part by the Pearl M. Stettler Award for Women Physicians and by a Clinician Scientist Award from the Johns Hopkins University School of Medicine. We thank Z. Deng for expert technical assistance.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles. To characterize the relationship between the genetic and epigenetic defects in PHP type 1b, we analyzed allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP type 1b and in affected and unaffected individuals from five multigenerational kindreds with PHP type 1b. All subjects with resistance to parathyroid hormone (PTH) showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A-containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. We found that affected and unaffected siblings in one kindred had inherited the same GNAS1 allele from their affected mother, evidence for dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who have inherited a defective maternal GNAS1 allele suggests that the genetic mutation may be incompletely penetrant, and it indicates that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP type 1b.
AB - Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles. To characterize the relationship between the genetic and epigenetic defects in PHP type 1b, we analyzed allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP type 1b and in affected and unaffected individuals from five multigenerational kindreds with PHP type 1b. All subjects with resistance to parathyroid hormone (PTH) showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A-containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. We found that affected and unaffected siblings in one kindred had inherited the same GNAS1 allele from their affected mother, evidence for dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who have inherited a defective maternal GNAS1 allele suggests that the genetic mutation may be incompletely penetrant, and it indicates that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP type 1b.
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U2 - 10.1086/377136
DO - 10.1086/377136
M3 - Article
C2 - 12858292
AN - SCOPUS:0042165833
SN - 0002-9297
VL - 73
SP - 314
EP - 322
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -