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Submitted on June 7, 2005
Accepted on August 2, 2005
Division of Pediatric Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Park Building, Suite 211, 600 N. Wolfe St., Baltimore, MD 21287-2520; The Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, MD; Weis Center for Research, The Geisinger Clinic, Danville, PA; Department of Neurosciences, The Johns Hopkins University School of Medicine, Baltimore, MD; Departments of Medicine and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Comparative Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD; Divisions of Endocrinology, Oncology and Human Cancer Genetics, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio; Department of Pediatric Endocrinology, The Cleveland Clinic Foundation, Cleveland, Ohio
* To whom correspondence should be addressed. E-mail: egermain{at}jhmi.edu.
Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS, a gene that encodes not only 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 AHO is termed pseudohypoparathyroidism (PHP) type 1a and is due to presumed tissue-specific paternal imprinting of Gs. 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 Gs as well as NESP55 and XLs, we created transgenic mice with disruption of exon 1 to investigate the effects of isolated loss of Gs. 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. Gs 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 Gs deficiency alone is sufficient to account for the hormone resistance of PHP type 1a.
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