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

Abstract

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