New mutation type in pseudohypoparathyroidism type Ia

Context The GNAS gene encodes the α‐subunit of the stimulatory G proteins, which play a crucial role in intracellular signal transduction of peptide and neurotransmitter receptors. Heterozygous inactivating maternally inherited mutations of GNAS (including translation initiation mutations, amino acid substitutions, nonsense mutations, splice site mutations and small insertions or deletions) lead to a phenotype in which Albright hereditary osteodystrophy is associated with pseudohypoparathyroidism type Ia. Objective We sought to identify the molecular defect in a patient who was thought to have PHP‐Ia. Methods and results The GNAS gene of a 5‐year‐old boy with brachydactily, mental retardation, pseudohypoparathyroidism and congenital hypothyroidism was investigated. We found a heterozygous inversion of exon 2 and part of intron 1 of de novo origin. Molecular studies of cDNA from blood RNA demonstrated that both the normal and the mutant variants were stable and that new splice‐sites were generated. Conclusion This report demonstrates the first evidence for an inversion at the GNAS gene responsible of pseudohypoparathyroidism type Ia.