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A disruptive mutation in exon 3 of the GNAS gene with albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsalpha-L deficiency.
J Clin Endocrinol Metab. 2007 May; 92(5):1764-8.JC

Abstract

OBJECTIVE

The GNAS gene encodes the alpha-subunit of stimulatory G proteins, which play a crucial role in intracellular signal transduction of peptide and neurotransmitter receptors. In addition to transcript variants that differ in their first exon due to different promoters, there are two long (Gsalpha-L) and two short (Gsalpha-S) splice variants, created by alternative splicing. Heterozygous inactivating maternally inherited mutations of GNAS lead to a phenotype in which Albright hereditary osteodystrophy is associated with pseudohypoparathyroidism type Ia.

METHODS AND RESULTS

The GNAS gene of a 10-yr-old girl with brachymetacarpia, mental retardation, normocalcemic pseudohypoparathyroidism, and hypothyroidism was investigated. We found a heterozygous insertion of an adenosine in exon 3 altering codon 85 and leading to a frame shift inducing a stop codon in exon 4. Molecular studies of cDNA from blood RNA demonstrated normal, biallelic expression of Gsalpha-S transcripts, whereas expression of Gsalpha-L transcripts from the maternal allele was reduced. Immunoblot analysis revealed a reduced Gsalpha-L protein level to about 50%, whereas the protein level of Gsalpha-S was unaltered. Furthermore, the Gsalpha protein activity in erythrocyte membranes was diminished to about 75% of normal. Both the reduced activity and the mutation were also found in the mother and the affected younger brother.

CONCLUSION

This report demonstrates the first evidence for a pathogenic mutation in exon 3 of the GNAS gene. The mutation is associated with a phenotype of Albright hereditary osteodystrophy and pseudohypoparathyroidism type Ia due to selective deficiency of Gsalpha-L and a partial reduction of Gsalpha activity.

Authors+Show Affiliations

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17299070

Citation

Thiele, Susanne, et al. "A Disruptive Mutation in Exon 3 of the GNAS Gene With Albright Hereditary Osteodystrophy, Normocalcemic Pseudohypoparathyroidism, and Selective Long Transcript Variant Gsalpha-L Deficiency." The Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 5, 2007, pp. 1764-8.
Thiele S, Werner R, Ahrens W, et al. A disruptive mutation in exon 3 of the GNAS gene with albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsalpha-L deficiency. J Clin Endocrinol Metab. 2007;92(5):1764-8.
Thiele, S., Werner, R., Ahrens, W., Hoppe, U., Marschke, C., Staedt, P., & Hiort, O. (2007). A disruptive mutation in exon 3 of the GNAS gene with albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsalpha-L deficiency. The Journal of Clinical Endocrinology and Metabolism, 92(5), 1764-8.
Thiele S, et al. A Disruptive Mutation in Exon 3 of the GNAS Gene With Albright Hereditary Osteodystrophy, Normocalcemic Pseudohypoparathyroidism, and Selective Long Transcript Variant Gsalpha-L Deficiency. J Clin Endocrinol Metab. 2007;92(5):1764-8. PubMed PMID: 17299070.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A disruptive mutation in exon 3 of the GNAS gene with albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsalpha-L deficiency. AU - Thiele,Susanne, AU - Werner,Ralf, AU - Ahrens,Wiebke, AU - Hoppe,Ute, AU - Marschke,Christine, AU - Staedt,Pia, AU - Hiort,Olaf, Y1 - 2007/02/13/ PY - 2007/2/15/pubmed PY - 2007/6/7/medline PY - 2007/2/15/entrez SP - 1764 EP - 8 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 92 IS - 5 N2 - OBJECTIVE: The GNAS gene encodes the alpha-subunit of stimulatory G proteins, which play a crucial role in intracellular signal transduction of peptide and neurotransmitter receptors. In addition to transcript variants that differ in their first exon due to different promoters, there are two long (Gsalpha-L) and two short (Gsalpha-S) splice variants, created by alternative splicing. Heterozygous inactivating maternally inherited mutations of GNAS lead to a phenotype in which Albright hereditary osteodystrophy is associated with pseudohypoparathyroidism type Ia. METHODS AND RESULTS: The GNAS gene of a 10-yr-old girl with brachymetacarpia, mental retardation, normocalcemic pseudohypoparathyroidism, and hypothyroidism was investigated. We found a heterozygous insertion of an adenosine in exon 3 altering codon 85 and leading to a frame shift inducing a stop codon in exon 4. Molecular studies of cDNA from blood RNA demonstrated normal, biallelic expression of Gsalpha-S transcripts, whereas expression of Gsalpha-L transcripts from the maternal allele was reduced. Immunoblot analysis revealed a reduced Gsalpha-L protein level to about 50%, whereas the protein level of Gsalpha-S was unaltered. Furthermore, the Gsalpha protein activity in erythrocyte membranes was diminished to about 75% of normal. Both the reduced activity and the mutation were also found in the mother and the affected younger brother. CONCLUSION: This report demonstrates the first evidence for a pathogenic mutation in exon 3 of the GNAS gene. The mutation is associated with a phenotype of Albright hereditary osteodystrophy and pseudohypoparathyroidism type Ia due to selective deficiency of Gsalpha-L and a partial reduction of Gsalpha activity. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/17299070/A_disruptive_mutation_in_exon_3_of_the_GNAS_gene_with_albright_hereditary_osteodystrophy_normocalcemic_pseudohypoparathyroidism_and_selective_long_transcript_variant_Gsalpha_L_deficiency_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2006-2122 DB - PRIME DP - Unbound Medicine ER -