Compound heterozygous mutations in the GNAS gene of a boy with morbid obesity, thyroid-stimulating hormone resistance, pseudohypoparathyroidism, and a prothrombotic state.

Abstract

CONTEXT:

Pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism are characterized by Albright's hereditary osteodystrophy (AHO), respectively, with and without hormone resistance. Both clinical conditions result from decreased expression or function of the alpha-subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase due to heterozygous inactivating mutations in GNAS. Homozygous GNAS defects have not been described.

OBJECTIVE:

A genetic and functional GNAS study was undertaken in a boy with morbid obesity (body mass index Z-score of 5 at the age of 3 yr, with a body fat fraction of 40%, which is more than twice normal), TSH resistance, pseudohypoparathyroidism, and a prothrombotic state.

RESULTS:

The boy was found to be a first case with a compound heterozygous GNAS defect: a de novo R231C mutation on the paternal allele and on the other allele a maternally inherited unique combination of three C to T nucleotide substitutions in exon 7 (I185I), intron 7 (IVS7 + 31), and exon 13 (N371N) leading to aberrant splicing of GNAS. Platelets of this boy displayed a pronounced Gsalpha hypofunction and were spontaneously hyperreactive resulting in a prothrombotic state due to extremely low cAMP levels.

CONCLUSION:

This report expands the human GNAS genotype-phenotype spectrum to include compound heterozygosity and a prothrombotic state.

• Authors: Kathleen Freson, Benedetta Izzi, Jaak Jaeken, Monique Van Helvoirt, Chantal Thys, Christine Wittevrongel, Francis de Zegher, Chris Van Geet
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 93 Issue 12 Pg. 4844-9 (Dec 2008) ISSN: 0021-972X [Print] United States
• PMID: 18796523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromogranins
• RNA, Messenger
• DNA
• Cyclic AMP
• GNAS protein, human
• GTP-Binding Protein alpha Subunits, Gs

Topics

• Adiposity (genetics, physiology)
• Blotting, Western
• Body Mass Index
• Body Weight
• Chromogranins
• Cyclic AMP (blood)
• DNA (genetics)
• Fibroblasts (metabolism)
• GTP-Binding Protein alpha Subunits, Gs (genetics)
• Humans
• Hyperphosphatemia (etiology)
• Hypocalcemia (etiology)
• Infant
• Male
• Mutation
• Obesity, Morbid (complications, genetics, pathology)
• Platelet Aggregation
• Platelet Function Tests
• Pseudohypoparathyroidism (complications, genetics)
• RNA, Messenger (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Thrombosis (complications, genetics)
• Thyroid Hormone Resistance Syndrome (complications, genetics)