The Coexistence of a Novel Inactivating Mutant Thyrotropin Receptor Allele with Two Thyroid Peroxidase Mutations: A Genotype-Phenotype Correlation

Abstract

TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele.

The Clinical Spectrum of Thyrotropin Receptor Gene (TSHR) Mutations

“…Coexistence of mutations in TPO (Sriphrapradang et al, 2011) and GNAS (Lado-Abeal et al, 2011), in addition to mutations in TSHR, has been reported in the same individuals. In those reports, the coexistence of mutated TPO and TSHR in the same individuals belonging to the same kindred did not aggravate the severity of the RTSH phenotype (Sriphrapradang et al, 2011); similar observations were made for the presence of a monoallelic TSHR mutation coexisting with a GNAS mutation (Lado-Abeal et al, 2011). It is therefore suggested that in cases where TSHR mutations do not explain the phenotype, additional genes that are involved in thyroid hormone synthesis be screened.…”

“…We found up to 2.4% carriers of two known mutations in a highly consanguineous population in the northern region of Israel (Tenebaum-Rakover et al, 2009). Moreover, the coexistence of two different novel mutations of TSHR in each of two separate clans has been shown (Sriphrapradang et al, 2011). In view of these data, it may be speculated that the occurrence of inactivating TSHR mutations in certain populations is not so rare, and therefore screening for TSHR mutations is indicated in cases with non-autoimmune subclinical hypothyroidism in those populations.…”

“…The affected patients are commonly identified by routine laboratory tests and are asymptomatic. Most of the described cases are heterozygous for TSHR mutations, but biallelic mutations have been reported as well (Kanda et al, 2006;Russo et al, 2000;Sriphrapradang et al, 2011;Tenenbaum-Rakover et al, 2009;Tonacchera et al, 2001Tonacchera et al, , 2007.…”

“…Heterozygous subjects carrying loss-of-function mutations in TSHR are commonly mildly affected, presenting with euthyroid hyperthyrotropinemia but with variable expressivity (Camilot et al, 2005;Sriphrapradang et al, 2011;Tenenbaum-Rakover et al, 2009). Heterozygotes are typically diagnosed with slightly increased TSH but normal free T 4 (FT 4 ) levels.…”

Severe post-partum autoimmune hypothyroidism associated with a novel loss-of-function mutation in intracellular domain of human thyrotropin receptor

“…Most of the mutations are missense mutations, but deletions and insertions have been identified as well [5].…”