Study on the pathogenesis for syndrome of resistance to thyroid hormone using cultured human skin fibroblasts.

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The syndrome of generalized resistance to thyroid hormone(GRTH)is characterized by reduced clinical and biochemical manifestations of thyroid hormone action relative to the circulating hormone levels. Several reports demonstrated abnormalities in beta isoform of T_3 receptor gene(c-erbA beta). However, a question how the mutation of c-erbA beta cause the clinical manifestation of the syndrome still remaied to be clarified. The current research aimed to uncover the pathogenesis of a syndrome of generalized resistance to thyroid hormone(GRTH)using cultured skin fibroblasts obtained from the patients. In the fitst year of investigation, we tried to clarify how the mutation in c-erbA beta affects the expression of other isoform of T_3 receptor gene(c-erbA alpha). We utilized reverse transcription-polymerase chain reaction(RT-PCR)to determine c-erbA mRNAs. We pick up two cases in family A which exibits one single nucleotide substitution in one allel of c-erbA beta gene. We also examined the exprtession of c-erbA a gene in fibroblasts from family B in which most of the coding region of c-erbA beta gene is deleted in both alleles. The result indicated that normal and mutated c-erbA beta genes are equally expressed in family A.In the case of family B, no c-erbA beta mRNA was detected. In both famity A and B, c-erbA alpha was expressed like in fibroblasts from normal subjects. From these results indicated hat the mutation does not affect the expression of normal c-erbA gene. Thus, we conculuded the pathogenesis of GRTH is unlikeky due to the abnormal expression of a normal allele of c-erbA beta and of c-erbA alpha. We next examined whether the type of mutation is related to the responsiveness to T_3 when the expressions of mRNAs for T_3 responsive genes are used as a marker of T_3 action. At first, we used the collagenase and the fibronetin as a marker, however, we gofound that these mRNA expression were altered by other factors than T<@2