title: Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a.
abstract: Albright hereditary osteodystrophy (AHO) is characterized by multiple somatic defects secondary to mutations in the GNAS1 gene. AHO patients with mutations on maternally inherited alleles are resistant to multiple hormones (e.g., PTH, TSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to presumed tissue-specific paternal imprinting of the alpha chain of G(s) as demonstrated in murine renal proximal tubule and fat cells. Studies in human tissues thus far revealed imprinting only in pituitary. Because mild hypothyroidism due to TSH resistance occurs in most PHP type 1a patients, we investigated whether Galpha(s) is imprinted in thyroid. Examination of eight normal thyroids demonstrated significantly greater expression from the maternal GNAS1 allele, with paternal Galpha(s) transcripts accounting for only 25.9-40.4%. Expression of NESP55, XLalpha(s), and 1A was uniallelic. We conclude that Galpha(s) is incompletely imprinted in the thyroid, which provides an explanation for mild TSH resistance in PHP type 1a.
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Park Building, Suite 211, 600 N. Wolfe Street, Baltimore, 21287-2520, MD, USA. egermain@jhmi.edu
authors.forename: Emily L
authors.initials: EL
authors.lastname: Germain-Lee
authors.forename: Chang Lin
authors.initials: CL
authors.lastname: Ding
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Deng
authors.forename: Janet L
authors.initials: JL
authors.lastname: Crane
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D001483:Base Sequence; D002864:Chromogranins; D017931:DNA Primers; D019205:GTP-Binding Protein alpha Subunits, Gs; D018392:Genomic Imprinting; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000378:metabolism*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*
chemical_list: D002864:Chromogranins; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins