Germline mutations of XXXX gene as cause of nonautoimmune subclinical hypothyroidism.

@entity1 @entity268 @entity70900 @entity1669 @entity63875 @entity509 @entity70899 @entity5010 @entity70898
Germline loss-of-function mutations of @entity5010 ( @entity5010 ) gene have been described in families with partial or complete TSH resistance. Large TSH elevations were generally found in the @entity1 with homozygous or compound heterozygous mutations. In this study, we sequenced the entire @entity5010 gene in a series of 10 unrelated @entity1 with slight (6.6-14.9 mU/liter) to moderate (24-46 mU/liter) elevations of serum TSH, associated with definitely normal free thyroid hormone concentrations. Thyroid volume was normal in all @entity1 , except two with a modest @entity509 . @entity1669 was excluded in all @entity1 on the basis of clinical and biochemical parameters. Eight @entity1 had at least one first-degree relative bearing the same biochemical picture. @entity5010 mutations were detected in 4 of 10 cases by analyzing DNA from peripheral leukocytes. A compound heterozygosity ( @entity63875 on maternal allele, and the novel mutation @entity70898 on the paternal one) was found in the @entity1 with the highest TSH levels. Only one @entity5010 allele was mutated in the remaining three cases, and no alterations in @entity5010 gene promoter were detected in all of these probands. A novel mutation ( @entity70899 ) was detected on the maternal allele in one @entity1 and in her monozygotic twin. Previously described inactive mutants, T655Delta and @entity70900 , were detected in the other two cases. When tested on several occasions, circulating TSH values fluctuating above the upper limit of the normal range could be shown in heterozygous subjects of these families. A dominant mode of inheritance of the biochemical alterations was detected in these cases. Mutant TSHRs were studied during transient expression in COS7 and HEK293T cells. Their TSH-independent @entity268 accumulation activities were very low or similar to mock-transfected cells, and no increases were seen after maximal hormone stimulation. Flow cytometry experiments showed a poor level of expression of all mutant TSHRs at the cell membrane. In conclusion, we found several loss-of-function mutations of @entity5010 , including two novel ones, in a series of unrelated @entity1 with slightly elevated TSH levels. Therefore, partial resistance to TSH action is a frequent finding among @entity1 with slight hyperthyrotropinemia of nonautoimmune origin. Germline mutations of @entity5010 may be associated with serum TSH values fluctuating above the upper limit of the normal range, also in the heterozygous state.
