Abstract | CONTEXT: 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.
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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)
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Chemical References |
- Chromogranins
- RNA, Messenger
- DNA
- Cyclic AMP
- GNAS protein, human
- GTP-Binding Protein alpha Subunits, Gs
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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)
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