Abstract
Mutations in the guanine nucleotide binding protein α subunit (Gsα) have been found in patients with pseudohypoparathyroidism (PHP). We have screened the Gsα gene for mutations in a Japanese patient with this disorder and identified a novel 4-base pair deletion in exon 7 in codons 189–190. This deletion causes a frameshift and if synthesis of a truncated form of Gsα occurred, it would likely be biologically inactive. The patient was heterozygous for this deletion. The patient’s mother and an unaffected brother were tested for the presence of this mutation. His mother had the same mutation, and although her serum calcium and parathyroid hormone levels were within the normal range, she had subcutaneous calcifications. Thus, this mutation appears to be necessary but not sufficient to cause the complete pseudohypoparathyroidism phenotype and thus, other unknown factors, either genetic or acquired, may be necessary for the full syndrome to occur.
Similar content being viewed by others
References
Gilman A.G. G proteins: transducers of receptor-generated signals. Ann. Rev. Biochem, 56: 615, 1987.
Spiegel A.M., Shenker A., Weinstein L.S. Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction. Endocr. Rev. 13: 536, 1992.
Conklin B.R., Bourne H.R. Structural elements of Gα subunits that interact with Gßγ, receptors, and effectors. Cell 73: 631, 1993.
Levine M.A., Jap T.S., Mauseth R.S., Downs R.W., Spiegel A.M. Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: biochemical, endocrine, and genetic analysis of Albright’s hereditary osteodystrophy in six kindreds. J. Clin. Endocrinol. Metab. 62: 497, 1986.
Carter A., Bardin C., Collins R., Simons C., Bray P., Spiegel A. Reduced expression of multiple forms of the a sub-unit of the stimulatory GTP-binding protein in pseudohypoparathyroidism type la. Proc. Natl. Acad. Sci. USA. 84: 7266, 1987.
Levine M.A., Downs Jr R.W. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Am. J. Med. 74: 545, 1983.
Spiegel A.M., Weinstein L.S., Shenker A. Abnormalities in G protein-coupled signal transduction pathways in human disease. J.Clin. Invest. 92: 1119, 1993.
Patten J.L., Johns D.R., Valle D., Eil C., Gruppuso P.A., Steele G., Smallwood P.M., Levine M.A. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N. Engl. J. Med. 20: 1412, 1990.
Weinstein L.S., Gejman P.V., Friedman E., Kadowaki T., Collins R.M., Gershon E.S., Spiegel A.M. Mutations of the Gsα-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc. Natl. Acad. Sci. USA. 87: 8287, 1990.
Weinstein L.S., Gejman P.V., Mazancourt P., American N., Spiegel A.M. A heterozygous 4-bp deletion mutation in the Gsα gene (GNAS1) in a patient with Albright hereditary osteodystrophy. Genomics 13: 1319, 1992.
Miric A., Vechio J.D., Levine M.A. Heterogeneous mutations in the gene encoding the α-subunit of the stimulatory G protein of adenylyl cyclase in Albright hereditary osteodystrophy. J. Clin. Endocrinol. Metab. 76: 1560, 1993.
Oude Luttikhuis M.E.M., Wilson L.C., Leonard J.V., Trembath R.C. Characterization of a de novo 43-bp deletion of the Gsa gene (GNAS1) in Albright hereditary osteodystrophy. Genomics 21: 455, 1994.
Iiri T., Herzmark P., Nakamoto J.M., Van Dop C., Bourne H.R. Rapid GDP release from Gsα in patients with gain and loss of endocrine function. Nature 371: 164, 1994.
Schwindinger W.F., Miric A., Zimmerman D., Levine M.A. A novel Gsα mutant in a patient with Albright hereditary osteodystrophy uncouples cell surface receptors from adenylyl cyclase. J. Biol. Chem. 269: 25387, 1994.
Myers R.M., Fischer S.G., Lerman L.S., Maniatis T. Nearly all single base substitutions in DNA fragments joined to a GC-clamp can be detected by denaturing gradient gel electrophoresis. Nucleic Acids Res. 13: 3131, 1985.
Kozasa T., Itoh H., Tsukamoto T., Kaziro Y. Isolation and characterization of the human Gsα gene. Proc. Natl. Acad. Sci. USA. 85: 2081, 1988.
Takeda K., Weiss R.E., Refetoff S. Rapid localization of mutations in the thyroid hormone reeeptor-ß gene by denaturing gradient gel electrophoresis in 18 families with thyroid hormone resistance. J. Clin. Endocrinol. Metab. 74: 712, 1992.
Iyota K., Takeda K., Matsuzuka F., Okabayashi T., Morita S., Kuma K., Hashimoto K. Absence of p53 mutation in Japanese patients with malignant thyroid lymphoma. J. Endocrinol. Invest. 17: 775, 1994.
Levine MA, Ahn T.G., Klupt S.F., Kaufman K.D., Smallwood P.M., Bourne HR., Sullivan K.A., Van Dop C. Genetic deficiency of the a subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy. Proc. Natl. Acad. Sci. USA. 85: 617, 1988.
Campbell R., Gosden C.M., Bonthron D.T. Parental origin of transcription from the human GNAS1 gene. J. Med. Genet. 31: 607, 1994.
Surani M.A. Influence of genomic imprinting on gene expression, phenotipic variations and development. Hum. Reprod. 6: 45, 1991.
Stog̈er R., Kubicka P., Liu C-G., Kafri T., Razin A., Cedar H., Barlow D.P. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 73: 61, 1993.
David S.J., Hughes H.E. Imprinting in Albright’s hereditary osteodystrophy. J. Med. Genet. 30: 101, 1993.
Schuster V., Kress W., Kruse K. Paternal and maternal transmission of pseudohypoparathyroidism type la in a family with Albright hereditary osteodystrophy: no evidence of genomic imprinting. J. Med. Genet. 31: 84, 1994.
Kehlenbach R.H., Matthey J., Huttner W.B. XLαs is a new type of G protein. Nature 372: 804, 1994.
Weinstein L.S., Shenker A. G protein mutations in human disease. Clin. Biochem. 26: 333, 1993.
Kinard R.E., Walton J.E., Buckwalter J.A. Pseudohypoparathyroidism. Report on a family with four affected sisters. Arch. Intern. Med. 139: 204, 1979.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yokoyama, M., Takeda, K., Iyota, K. et al. A 4-base pair deletion mutation of Gsα gene in a Japanese patient with pseudohypoparathyroidism. J Endocrinol Invest 19, 236–241 (1996). https://doi.org/10.1007/BF03349874
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03349874