A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene.
Albright hereditary osteodystrophy is caused by heterozygous inactivating mutations in GNAS, a gene that encodes not only the alpha-chain of Gs (Galphas), but also NESP55 and XLalphas through use of alternative first exons. Patients with GNAS mutations on maternally inherited alleles are resistant to multiple hormones such as PTH, TSH, LH/FSH, GHRH, and glucagon, whose receptors are coupled to Gs. This variant of Albright hereditary osteodystrophy is termed pseudohypoparathyroidism type 1a and is due to presumed tissue-specific paternal imprinting of Galphas. Previous studies have shown that mice heterozygous for a targeted disruption of exon 2 of Gnas, the murine homolog of GNAS, showed unique phenotypes dependent on the parent of origin of the mutated allele. However, hormone resistance occurred only when the disrupted gene was maternally inherited. Because disruption of exon 2 is predicted to inactivate Galphas as well as NESP55 and XLalphas, we created transgenic mice with disruption of exon 1 to investigate the effects of isolated loss of Galphas. Heterozygous mice that inherited the disruption maternally (-m/+) exhibited PTH and TSH resistance, whereas those with paternal inheritance (+/-p) had normal hormone responsiveness. Heterozygous mice were shorter and, when the disrupted allele was inherited maternally, weighed more than wild-type littermates. Galphas protein and mRNA expression was consistent with paternal imprinting in the renal cortex and thyroid, but there was no imprinting in renal medulla, heart, or adipose. These findings confirm the tissue-specific paternal imprinting of GNAS and demonstrate that Galphas deficiency alone is sufficient to account for the hormone resistance of pseudohypoparathyroidism type 1a.
Germain-Lee
Emily L
EL
Division of Pediatric Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Park Building, Suite 211, 600 North Wolfe Street, Baltimore, Maryland 21287-2520, USA. egermain@jhmi.edu
Schwindinger
William
W
Crane
Janet L
JL
Zewdu
Rediet
R
Zweifel
Larry S
LS
Wand
Gary
G
Huso
David L
DL
Saji
Motoyasu
M
Ringel
Matthew D
MD
Levine
Michael A
MA
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001827:Body Height; D001835:Body Weight; D001842:Bone and Bones / Q000473:pathology; D002864:Chromogranins; D004195:Disease Models, Animal; D005091:Exons; D005298:Fertility; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018392:Genomic Imprinting; D006801:Humans; D008098:Litter Size; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D010281:Parathyroid Hormone / Q000494:pharmacology; D010641:Phenotype; D016019:Survival Analysis; D013972:Thyrotropin / Q000494:pharmacology
D002864:Chromogranins; D010281:Parathyroid Hormone; D013972:Thyrotropin; C406732:GNAS protein, human; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases