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Biomedical subjects

Akira Hishinuma

Publications and source records attributed to Akira Hishinuma.

13 recordsLinked to original sources
PubMed2006

Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient.

Constitutively activating thyrotropin receptor (TSHR) germline mutations have been identified as a molecular cause of congenital hyperthyroidism. We here describe a Japanese woman who had presented with severe hyperthyroidism and advanced bone age as a neonate. She underwent neurosurgical intervention for craniosynostosis, and presented with perodactylia and mild mental retardation with hydrocephalus. Hyperthyroidism has been refractory to antithyroid drug therapy in the absence of antithyrotropin receptor antibodies during follow-up of 20 years, resulting in an enlarged goiter. Analysis of the patient's genomic DNA showed a heterozygous thymine-to-adenine point mutation in exon 10 of TSHR at position 1535 which was not present in the parents' DNA. This mutation, changing leucine to glutamine in codon 512 in the third transmembrane region, was previously identified as a somatic mutation in toxic thyroid nodules and was shown to increase basal cAMP production in vitro. To our knowledge, this is the first report of a germline mutation of TSHR causing sporadic congenital nonautoimmune hyperthyroidism in a Japanese patient.

Adult↗
PubMed2006

Haplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan.

CONTEXT: Thyroglobulin (Tg) mutations were previously believed to be rare, resulting in congenital goitrous hypothyroidism. However, an increasing number of patients with Tg mutations, who are euthyroid to mildly hypothyroid, have been identified in Japan. OBJECTIVES: The purpose of this study was to investigate whether the three frequently found Tg mutations, namely C1058R, C1245R, and C1977S, were caused by a founder effect. RESULTS: We found 26 different mutations within the Tg gene in 52 patients from 41 families. Thirty-five patients were homozygous for the mutations, whereas the others were compound heterozygous. The occurrence of Tg mutation within the general Japanese population is one in 67,000. Patients with the C1245R mutation were found throughout Japan, whereas those with the C1058R mutation were confined to a small village on a southern island, and those with the C1977S mutation were restricted to a city. The eight patients with the C1058R mutation and the seven patients with the C1977S mutation all showed the same combinations of 18 single-nucleotide polymorphisms in the coding region of the Tg gene, which would appear in one in 810 million and one in 37 billion, respectively, control subjects. CONCLUSIONS: The frequently found mutations, C1058R and C1977S, were caused by founder effects. This result suggests that Tg mutations may provide a genetic basis for the cause of familial euthyroid goiter.

Founder Effect↗
PubMed2006

A novel compound heterozygous mutation in the thyroglobulin gene resulting in congenital goitrous hypothyroidism with high serum triiodothyronine levels.

Thyroglobulin abnormality is a rare cause of congenital hypothyroidism and only a limited number of mutations in the thyroglobulin gene have been reported. We analyzed the thyroglobulin gene in a patient with congenital goitrous hypothyroidism. This girl was identified with hyperthyrotropinemia in a neonatal mass-screening test. The patient had goiter, and her body weight gain was poor. Distal femoral epiphysis was absent on roentgenography. Her serum thyroxine level was low; however, her triiodothyronine level was high. Autoantibodies against triiodothyronine, thyroid peroxidase, and thyroglobulin were all negative. Her serum thyroglobulin level was undetectable. The thyroglobulin gene from the genomic DNA of the patient was analyzed by direct sequencing. Two novel heterozygous missense mutations, Cys1897Tyr (exon 31) and Arg2336Gln (exon 40), were found in the patient. The former mutation was derived from her mother, suggesting a compound heterozygous state. Normal triiodothyronine and low thyroxine concentrations are often observed in patients with thyroglobulin gene mutations. We considered that some patients with thyroglobulin abnormality might have high triiodothyronine levels. In cases of congenital goitrous hypothyroidism with normal-to-high triiodothyronine levels and low serum thyroglobulin levels, thyroglobulin abnormality should be considered.

Amino Acid Substitution↗
PubMed2005

High incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations.

In this paper, we report the high prevalence of thyroid malignancy in patients with thyroglobulin mutations in Japan. Mutations of the thyroglobulin gene cause defective thyroid hormone synthesis, resulting in congenital hypothyroidism. Since our report in 1999 on the thyroglobulin mutations C1264R and C1996S, we have identified 14 adult patients (7 males and 7 females) from 9 unrelated families. They visited hospitals for treatment of huge goiters that first appeared in childhood. Persistent growth of the thyroid gland, probably caused by thyrotropin (TSH) stimulation, partially compensated thyroid hormone production, resulting in lowered serum TSH concentrations in turn. Consequently, many patients had to undergo multiple operations. Of 11 patients who had undergone surgery, 7 had thyroid cancers. Of five patients whose thyroid tissue was available, we found a heterozygous activating mutation, either V599E or K600E, in cancerous tissue from each of 2 patients. From these observations, we conclude that goiter resulting from thyroglobulin mutations is associated with thyroid cancer.

Adolescent↗
PubMed2005

[Thyroglobulin gene abnormalities].

Congenital hypothyroidism is caused either by abnormal development of thyroid glands or by inborn errors of thyroid hormone synthesis. Thyroglobulin mutations which caused overt Cretins with physical and mental development impairment were once believed rare. However, since the discovery of mild hypothyroidism due to thyroglobulin mutations, 54 cases from 43 families were identified in Japan. The patients presented either transient elevation of serum TSH during infancy or growing giant goiters from childhood. Among 15 patients who were born after initiation of neonatal screening in 1979, 13 patients were identified by high serum TSH. In contrast, the major manifestation in patients born before 1979 is persistent growth of goiters with euthyroidism or subclinical hypothyroidism. Among 25 mutations, Cys1264Arg and Cys1077Arg are hot spots. The Cys1264Arg patients were found all over Japan, but the Cys1077Arg patients were confined to a small village of a southern island in Japan. The occurrence of the thyroglobulin mutations in the general population is 1/67,000. The pathogenesis of abnormal thyroglobulin is defective intracellular transport. The histological findings include empty colloid in the follicles and distended ER filling the entire cytoplasm of the thyrocytes. An in vitro expression study showed that abnormal thyroglobulin was not secreted from cultured cells. Because of persistent growth of the thyroid, 25 patients underwent surgical treatment. Among them, 11 patients suffered from thyroid cancers, most of which were of the papillary type. We found two BRAF activating mutations Val599Glu and Cys600Gln in five patients tested. In conclusion, we found many patients with thyroglobulin mutations in Japan. They were found by high serum TSH at neonatal screening or persistent growth of goiters in adults. Surgical treatments were inevitable, and 40% of the removed thyroids contained thyroid cancers, some of which were caused by activating mutations of the BRAF gene.

Adult↗
PubMed2004

TTF-2 stimulates expression of 17 genes, including one novel thyroid-specific gene which might be involved in thyroid development.

Thyroid dysgenesis is the most frequent cause of congenital hypothyroidism, but its molecular pathophysiology is largely unknown. Our hypothesis that some genes downstream to thyroid transcription factor-2 (TTF-2) might be responsible for development of the thyroid prompted us to identify genes whose expression is stimulated by TTF-2. PCR products of cDNA clones obtained by a subtraction PCR method in TTF-2 expressing cell lines were screened with labeled cDNA by microarray analysis. We isolated 17 genes up-regulated by TTF-2, which were subsequently confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). One of them is a novel gene designated T1560 that showed a highly thyroid-specific expression pattern. Luciferase reporter assays showed that expression of all of the 14 genes tested was stimulated by both TTF-2 and TTF-1, another thyroid-specific transcription factor. Our results have important implications for understanding normal thyroid development as well as the molecular defects underlying thyroid dysgenesis.

Amino Acid Sequence↗
PubMed2004

Transient hypothyroidism or persistent hyperthyrotropinemia in neonates born to mothers with excessive iodine intake.

Perinatal exposure to excess iodine can lead to transient hypothyroidism in the newborn. In Japan, large quantities of iodine-rich seaweed such as kombu (Laminaria japonica) are consumed. However, effects of iodine from food consumed during the perinatal period are unknown. The concentration of iodine in serum, urine, and breast milk in addition to thyrotropin (TSH), free thyroxine (FT(4)), and thyroglobulin was measured in 34 infants who were positive at congenital hypothyroidism screening. Based on the concentration of iodine in the urine, 15 infants were diagnosed with hyperthyrotropinemia caused by the excess ingestion of iodine by their mothers during their pregnancy. According to serum iodine concentrations, these infants were classified into group A (over 17 microg/dL) and group B (under 17 microg/dL) of serum iodine. During their pregnancies these mothers consumed kombu, other seaweeds, and instant kombu soups containing a high level of iodine. It was calculated that the mothers of group A infants ingested approximately 2300-3200 microg of iodine, and the mothers of group B infants approximately 820-1400 microg of iodine per day during their pregnancies. Twelve of 15 infants have required levo-thyroxine (LT(4)) because hypothyroxinemia or persistent hyperthyrotropinemia was present. In addition, consumption of iodine by the postnatal child and susceptibility to the inhibitory effect of iodine may contribute in part to the persistent hyperthyrotropinemia. We propose that hyperthyrotropinemia related to excessive iodine ingestion by the mother during pregnancy in some cases may not be transient.

Adult↗
PubMed2003

Partial iodide organification defect caused by a novel mutation of the thyroid peroxidase gene in three siblings.

BACKGROUND: Three siblings with goitre and latent to mild hypothyroidism were suspected of having thyroid peroxidase (TPO) abnormality. Direct sequencing of their genomic DNAs showed two novel mutations of the TPO gene, one of which was G1687T (Gly533Cys; exon 9) and the other 1808-13del (Asp574/Leu575del; exon 10). The two mutations were compound heterozygous, as the former was found in their father's DNA as heterozygous, and the latter was found in DNA from their mother, also as heterozygous. As Gly533 and Asp574/Leu575 were well-conserved amino acids in the peroxidase superfamily, Gly533Cys- and Asp574/Leu575del-TPOs were thought to be affected structurally or functionally. In expression studies using CHO-Kl cells and mRNAs introduced with individual mutations, both mutated TPO proteins were expressed at the same molecular size as wild-type TPO and had enzyme activity, although Gly533Cys-TPO was slightly lower in efficiency of expression and more degenerative than wild-type TPO. METHODS: We examined the localization of both mutated TPOs. Gly533Cys-TPO was located on the endoplasmic reticulum (ER) and nuclear envelope but not on the plasma membrane, whereas Asp574/Leu575del-TPO was located not only on the ER and nuclear envelope but also on the plasma membrane, as wild-type TPO. Nevertheless, only one point differed between Asp574/Leu575del- and wild-type TPOs: the mutated TPO was expressed on the plasma membrane surface at less than half the rate of wild-type TPO. RESULTS: Gly533Cys-TPO synthesized almost no thyroid hormone because of its defective localization on the apical membrane surface of thyrocytes, whereas Asp574/Leu575del-TPO performed thyroid hormone synthesis at a rate of less half that of wild-type TPO. In cotransfection experiments using three combinations of wild-type and G1687T-mRNAs, wild-type and 1808-13del-mRNAs, and G1687T-, 1808-13del-mRNAs, the three kinds of mRNAs were considered to have no influence on cell surface TPO expression of another mRNA when a 50%-maximal amount of each mRNA was transfected. When a larger amount of each mRNA was transfected, the former two combinations showed the level of cell surface TPO expression obtained from the saturating amount of wild-type mRNA, whereas the last combination of mutated mRNAs covered only about half of the expression level. CONCLUSION: Defective thyroid hormone production resulting from the abnormal TPOs was at a level that caused latent hypothyroidism when the patients were born. With their growth, thyroid hormone volume gradually became inadequate and their thyroid gland enlarged compensatorily.

Animals↗
PubMedDate not supplied

Genetic modification of cold-preserved renal grafts using HSP70 or bcl-2 HVJ-liposome method.

BACKGROUND: We tested the hypothesis that the best time for genetic modification is while the cell viability of the graft is reduced for long-term preservation. The hemagglutinating virus of Japan (HVJ)-liposome method, a nonviral gene transfer technique, was used with a luciferase gene to test the efficacy of protein induction under the critical preservation time. Furthermore, we tested this genetic modification with heat shock protein (HSP) 70 or bcl-2 genes to prevent primary nonfunction (PNF) after long-term preservation. METHODS: Orthotopic rat renal transplantation (RT) was performed using the cuff technique in the syngeneic combination of Lew (major histocompatible complex, haplotype: RT1(l)). Rat kidney grafts were preserved for 24 or 48 h in University of Wisconsin (UW) or Ringer's lactate solution using HVJ method with the luciferase gene. Rats with gene-transfected kidneys were re-laparotomized 48 h after transplantation to estimate the lack of arterial flow in the graft and killed for histological evaluation of the degree of PNF luciferase intensity assay. Then, two functional genes (HSP70 or bcl-2) were tested for the occurrence of PNF and histological and immunohistochemical analysis of the grafted kidneys preserved for 48 h in the UW solution. RESULTS: In the kidneys preserved for 24 h, 50% of the Ringer's lactate group had PNF; but all of the UW group had sufficient blood flow. The graft viability was well corrected by the degree of luciferase intensity. The PNF rate was significantly suppressed in the bcl-2 gene-transfer group, and tended to be reduced in the HSP70 group. CONCLUSIONS: The HVJ-liposome method effectively induced the foreign gene for kidney grafts even in the cold-preservation solution. Induction of bcl-2 or the HSP70 gene reduced the occurrence of PNF in the rat renal graft. The results suggest that gene transfer not only maintains graft viability, but also graft activation.

Animals↗