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A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene.
Endocrinology. 2005 Nov; 146(11):4697-709.E

Abstract

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.

Authors+Show Affiliations

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.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16099856

Citation

Germain-Lee, Emily L., et al. "A Mouse Model of Albright Hereditary Osteodystrophy Generated By Targeted Disruption of Exon 1 of the Gnas Gene." Endocrinology, vol. 146, no. 11, 2005, pp. 4697-709.
Germain-Lee EL, Schwindinger W, Crane JL, et al. A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology. 2005;146(11):4697-709.
Germain-Lee, E. L., Schwindinger, W., Crane, J. L., Zewdu, R., Zweifel, L. S., Wand, G., Huso, D. L., Saji, M., Ringel, M. D., & Levine, M. A. (2005). A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology, 146(11), 4697-709.
Germain-Lee EL, et al. A Mouse Model of Albright Hereditary Osteodystrophy Generated By Targeted Disruption of Exon 1 of the Gnas Gene. Endocrinology. 2005;146(11):4697-709. PubMed PMID: 16099856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. AU - Germain-Lee,Emily L, AU - Schwindinger,William, AU - Crane,Janet L, AU - Zewdu,Rediet, AU - Zweifel,Larry S, AU - Wand,Gary, AU - Huso,David L, AU - Saji,Motoyasu, AU - Ringel,Matthew D, AU - Levine,Michael A, Y1 - 2005/08/11/ PY - 2005/8/16/pubmed PY - 2005/12/13/medline PY - 2005/8/16/entrez SP - 4697 EP - 709 JF - Endocrinology JO - Endocrinology VL - 146 IS - 11 N2 - 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. SN - 0013-7227 UR - https://www.unboundmedicine.com/medline/citation/16099856/A_mouse_model_of_albright_hereditary_osteodystrophy_generated_by_targeted_disruption_of_exon_1_of_the_Gnas_gene_ L2 - https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2005-0681 DB - PRIME DP - Unbound Medicine ER -