A TSHβ Variant with Impaired Immunoreactivity but Intact Biological Activity and Its Clinical Implications.

Background: Thyrotropin (TSH) deficiency caused by TSHβ gene mutations is a rare form of congenital central hypothyroidism. Nine different TSHβ gene mutations have been reported, all with clinical manifestations. The aim was to identify the genetic cause of undetectable TSH levels in two siblings with clinical euthyroidism. Methods: Two brothers born to consanguineous Pakistani parents presented with undetectable serum TSH but normal iodothyronine concentrations and no clinical signs of hypothyroidism. Direct sequencing of the TSHβ gene, functional and immunological studies, protein homology modeling, and population frequency analysis were performed to characterize the cause of undetectable TSH in this family. Results: Direct sequencing of the TSHβ gene revealed that the two brothers were homozygous for a single nucleotide substitution (c.223A>G) resulting in the replacement of arginine 55 with glycine (R55G). This variant was found in 12 out of 5008 alleles in the 1000 Genomes project (all South Asian). ...