We have examined the c-erbAfl thyroid hormone receptor gene in a kindred, G.H., with a member, patient G.H., who had a severe form of selective pituitary resistance to thyroid hormones (PRTH). This patient manifested inappropriately normal thyrotropin-stimulating hormone, markedly elevated serum free thyroxine (T4) and total triiodothyronine (T3), and clinical hyperthyroidism. The complete c-erbAfil coding sequence was examined by a combination of genomic and cDNA cloning for patient G.H. and her unaffected father. A single mutation, a guanine to adenine transition at nucleotide 1,232, was found in one allele of both these members, altering codon 311 from arginine to histidine. In addition, a half-sister of patient G.H. also harbored this mutant allele and, like the father, was clinically normal. The G.H. receptor, synthesized with reticulocyte lysate, had significantly defective T3-binding activity with a K. of -5 X 108 M-l. RNA phenotyping using leukocytes and fibroblasts demonstrated an equal level of expression of wild-type and mutant alleles in patient G.H. and her unaffected father. Finally, the G.H. receptor had no detectable dominant negative activity in a transfection assay. Thus, in contrast to the many other ,8-receptor mutants responsible for the generalized form of thyroid hormone resistance, the G.H. receptor appeared unable to antagonize normal receptor function. These results suggest that the arginine at codon 311 in c-erbA,6 is crucial for the structural integrity required for dominant negative function. The ARG-31 1-HIS mutation may contribute to PRTH in patient G.H. by inactivating a P-receptor allele, but it cannot be the sole cause of the disease. (J. Clin. Invest. 1993. 91:538-546.)
Riboflavin deficiency in weanling rats causes a metabolic disorder characterized by failure to oxidize fatty acids. The disorder is similar to that seen in several human diseases, some of which are responsive to pharmacological doses of riboflavin. Previous analysis of the riboflavin-deficient rat has shown that the failure of fatty acid oxidation is due to a decrease in the activity of the acyl-CoA dehydrogenases of beta-oxidation. The activity of these flavoenzymes in liver rapidly decreases when a riboflavin-deficient diet is initiated. The objectives of these experiments were to analyse the effects of starvation on liver mitochondria isolated from the riboflavin-deficient rat. Our studies show that the decreased mitochondrial fatty acid oxidation induced by riboflavin deficiency is partially reversed by starvation. The extent of this reversal is proportional to the duration of starvation. The starvation-associated increase in fatty acid oxidation is mediated by an increase in the mitochondrial short-chain acyl-CoA dehydrogenase activity. The activity of this enzyme is increased such that the ratio of short-chain acyl-CoA dehydrogenase apoenzyme to holoenzyme does not change. We conclude that short-chain acyl-CoA dehydrogenase activity is limiting for fatty acid oxidation when its activity falls below a critical point. The increased mitochondrial specific activity of short-chain acyl-CoA dehydrogenase during starvation may result from an increased availability of flavin coenzyme or an increase in enzyme catalytic efficiency.
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