Studies on Mono- and Diiodohistidine. II. CONGENITAL GOITROUS HYPOTHYROIDISM WITH THYROGLOBULIN DEFECT AND IODOHISTIDINE-RICH IODOALBUMIN PRODUCTION

Abstract

A B S T R A C T Butanol-insoluble iodinated compounds in the urine of patients with congenital goiters have been generally regarded as iodopeptides. Monoiodohistidine (MIH) and diiodohistidine (DIH) were identified from the urine of four patients with congenital goitrous hypothyroidism. From radioiodine studies, 40-70% of the urinary radioactivity was in the iodide-free fraction from which about 40% was identified as MIH and DIH by crystallizations to a constant specific activity.Iodotyrosines were simultaneously identified in the urine. However the presence of an iodotyrosine-deiodinase activity was demonstrated in the two removed goiters with a normal Km for MIT. In vivo iodotyrosine deiodination was normal for hypothyroid subjects.No thyroglobulin was identified in the thyroids from these patients. The major iodoprotein was iodoalbumin which, after in vivo labeling, contained 84-89% of the total soluble protein radioactivity. The thyroxine content of the goiter iodoalbumins and other iodoproteins was extremely low.Iodohistidines were identified in comparable proportions in the iodoalbumin and in the other iodoproteins isolated from each goiter. The average iodohistidine content of these proteins as crystallizable MIH and DIH was in the individual cases 15 and 4% of the in vivo incorporated radioiodine. DIH was identified in all iodoprotein fractions. The mean DIH/MIH ratios from the individual cases were 1.16 and 0.35. The corresponding DIT/MIT ratios were 3.19 and 1.45, respectively.The major consequence of this thyroglobulin defect is the iodination of inappropriate proteins (mainly albumin) resulting in low yields of thyroxine and high Received for publication 6 March 1972 and in revised form 19 September 1972. yields of iodohistidines. Iodohistidines from the goiter iodoproteins were not deiodinated and, at least for MIH, were quantitatively excreted in the urine of these patients. From the MIH iodoalbumin content and the MIH urinary excretion, goiter iodoalbumin turnover estimates were made and, although elevated, could not maintain a normal thyroxine secretion.The urinary excretion of iodohistidines easily demonstrated by column chromatography is offered as a test for detecting this variety of congenital goiter.

Normal Level of Thyroglobulin Messenger Ribonucleic Acid ina Human Congenital Goiter with Thyroglobulin Deficiency*

“…The probe was a human Tg cDNA clone labeled with 32 P by nick translation. Hybridization was performed in sealed capillaries, as described previously (28), with a 10 6 -fold excess of RNA. Rot is expressed as moles of nucleotides in RNAxtime (seconds).…”

“…The clinical and biological criteria defining a congenital goiter with Tg deficiency are the following: presence of a congenital goiter, hypothyroidism (low serum T 4 ), negative perchlorate test, undetectable serum Tg, absent or greatly reduced levels of 19S Tg in thyroid extracts, and presence of iodinated albumin in serum (high protein-bound iodine) and of iodohistidine in urine (28,29). A qualitative defect of Tg, where the protein, although present, would be unable to perform its normal function of thyroid hormone precursor, would cause the same abnormalities, except that significant amounts of immunoreactive Tg would be found in both serum and thyroid gland.…”

“…The coexistence of goiter with high serum TSH levels, hypothyroidism, and undetectable serum Tg levels was highly suggestive of the presence of a congenital defect of Tg production. A further argument in favor of this diagnosis was provided by the demonstration of high levels of iodohistidines in the patients' urine (28,29). Iodohistidines were identified in every urine sample analyzed, and the total iodohistidine content varied between 12.8 and 24.3 ng I/liter, representing 14-25% of the total iodine in the urine (normal, <5%) (28,29).…”

“…A further argument in favor of this diagnosis was provided by the demonstration of high levels of iodohistidines in the patients' urine (28,29). Iodohistidines were identified in every urine sample analyzed, and the total iodohistidine content varied between 12.8 and 24.3 ng I/liter, representing 14-25% of the total iodine in the urine (normal, <5%) (28,29). The genetic nature of the disease was ascertained by the fact that both siblings had exactly the same clinical and biological abnormalities.…”

Studies on Mono- and Diiodohistidine. I. THE IDENTIFICATION OF IODOHISTIDINES FROM THYROIDAL IODOPROTEINS AND THEIR PERIPHERAL METABOLISM IN THE NORMAL MAN AND RAT

“…In human congenital goiters however, iodo-compounds have been isolated from thyroid (14)(15)(16)(17), blood (16,18,19), and urine (14,20,21) as noniodide, butanol-insoluble, unknown compounds. We have identified large amounts of MIIH and DIH among similar compounds in these congenital goiters (22). Therefore the question arose as to whether these findings were specific for this pathological condition.…”