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A Mouse Model of Albright Hereditary Osteodystrophy Generated by Targeted Disruption of Exon 1 of the Gnas Gene

Department of Pediatrics, Division of Pediatric Endocrinology (E.L.G.-L., J.L.C., R.Z.), The Ilyssa Center for Molecular and Cellular Endocrinology (E.L.G.-L., J.L.C., R.Z.), Departments of Neurosciences (L.S.Z.), Medicine and Psychiatry (G.W.), and Comparative Medicine (D.L.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-2520; Weis Center for Research (W.S.), The Geisinger Clinic, Danville, Pennsylvania 17822; Divisions of Endocrinology, Oncology, and Human Cancer Genetics (M.S., M.D.R.), The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio 43210; and Department of Pediatric Endocrinology (M.A.L.), The Cleveland Clinic Foundation, Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Emily L. Germain-Lee, 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. E-mail: egermain{at}jhmi.edu.

Albright hereditary osteodystrophy is caused by heterozygous inactivating mutations in GNAS, a gene that encodes not only the -chain of Gs (G_s), but also NESP55 and XLs 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 G_s. 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 G_s as well as NESP55 and XLs, we created transgenic mice with disruption of exon 1 to investigate the effects of isolated loss of G_s. 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. G_s 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 G_s deficiency alone is sufficient to account for the hormone resistance of pseudohypoparathyroidism type 1a.

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