Papers - Narumi, Satoshi

Two Novel SLC5A5 Variants (Q263L and G350D) Causing Congenital Hypothyroidism

Abe K., Koizumi M., Kogai T., Ida S., Sugisawa C., Kawai M., Hasegawa T., Narumi S.

Thyroid 35 ( 3 ) 335 - 337 2025

ISSN  10507256

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SLC5A5 encodes sodium-iodide symporter (NIS), which transports inorganic iodide into thyroid cells. Biallelic loss-of-function variants in SLC5A5 cause thyroid dyshormonogenesis due to iodide transport defect (ITD). We report a Japanese sibling with ITD carrying novel compound heterozygous SLC5A5 variants (p. [Gln263Leu]; [Gly350Asp]). The elder brother was diagnosed with congenital hypothyroidism (CH) through newborn screening (NBS), while the younger brother, with a negative NBS result, developed CH-related symptoms at age 3 months. We characterized the two variant NIS proteins in vitro and negligible iodide transport capacity of both proteins. These findings provide unique evidence for the structure-function relationship of the NIS protein.

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Epigenetic modifications and their roles in pediatric brain tumor formation: emerging insights from chromatin dysregulation

Kawata K., Chapman O.S., Narumi S., Kawauchi D.

Frontiers in Oncology 15   1569548 2025

ISSN  2234-943X

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Pediatric brain tumors, the most devastating cancers affecting children, are believed to originate from neural stem/progenitor cells in developing brain. In precise timing and specific regions during the brain development, chromatin deregulation plays crucial roles in redirecting normal neuronal differentiation pathways toward tumorigenesis. Indeed, epigenomic abnormalities are thought to be more important for brain tumor formation especially in children than adults, as pediatric brain tumors generally exhibit fewer genetic mutations compared to adult brain tumors. Given the small number of mutations, targeting such limited alterations involved in cancer epigenomes is expected to be more effective in pediatric brain tumors. The mechanisms of cancer epigenomes include mutation or dysregulation of chromatin remodelers, histone modifiers, histones themselves, and DNA methylation enzymes. Furthermore, genomic rearrangements and/or higher-order chromatin topology also contribute to these epigenomic mechanisms. These mechanisms are commonly observed in various types of pediatric brain tumors. However, alterations in chromatin regulatory factors differ across tumor types, reflecting the unique epigenetic landscapes shaped by their tumor origins. Accordingly, clarifying their functional similarities and differences across tumor types could offer valuable insights for finding new therapeutic strategies. Thus, this review article focuses on elucidating how pediatric brain tumors arise from epigenomic deregulation and what epigenetic molecules or mechanisms could serve as therapeutic targets.

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Psychosocial and menstrual correlates of premenstrual disorders: A community‐based study

Shiori Itoi, Makiko Sampei, Takayuki Tatsumi, Yutaka Osuga, Kaori Koga, Satoshi Narumi, Naho Morisaki

International Journal of Gynecology & Obstetrics  2025

ISSN  00207292

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Objective: To assess the background, psychosocial, and menstrual factors associated with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) in a community-based cohort. Methods: A prospective cohort study was conducted using data from users of a menstrual tracking application. Participants were classified into control, PMS, or PMDD groups based on responses to the Japanese version of the premenstrual symptoms screening tool (PSST). Primary outcomes included background factors (e.g., healthcare literacy, stress coping), psychosocial measures (psychological distress, sleep quality, and work–home balance), and menstrual characteristics (average cycle length [CL], CL variability, abnormal cycle length, and menstrual symptoms). Age-adjusted multinomial logistic regression models were used to examine associations. Results: A total of 7227 individuals were included; 23% met criteria for PMS and 10% for PMDD. Both PMS and PMDD were associated with younger age, smoking history (current and past), more adverse childhood experiences, lower healthcare literacy, and higher maladaptive coping scores. PMDD was additionally linked to being married and co-residing with children, while PMS was associated with alcohol consumption. Both groups reported higher levels of psychological distress, poor sleep quality, and negative work–home balance. Although the prevalence of abnormal cycle length did not differ between groups, menstrual symptom burden was greater in both PMS and PMDD. Conclusion: Premenstrual disorders are associated with a wide range of sociodemographic and psychosocial difficulties. Although menstrual irregularities were similar across groups, menstrual symptom burden was markedly higher. These findings underscore the need for targeted, multidisciplinary support.

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Incidence of Deformational Plagiocephaly in Patients of Facial Contouring Surgery

Kanayama C., Sakamoto Y., Chi D., Numasawa Y., Narumi S., Miwa T.

Journal of Craniofacial Surgery  2025

ISSN  10492275

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Deformational plagiocephaly (DP), a distortion of a baby’s head shape due to sleeping position, can cause ear malposition, facial asymmetry, and malocclusion. Helmet therapy only surfaced as a recommended treatment in severe cases. However, the number of patients who have grown up with severe deformities without treatment has increased. It is unclear whether these deformities spontaneously resolve during growth. This study investigated the incidence of examining cranial deformities in patients seeking facial contour surgery. Patients presenting with facial asymmetry, jaw deformity, or other facial concerns were included. Complaints were categorized as malar asymmetry, lateral malar protrusion, or anterior malar protrusion. DP was classified using the Argenta system based on cone-beam CT images. Among patients with malar asymmetry (n = 32), Type IV deformities were most frequent (84.4%), followed by Type I (12.5%) and Type II (3.1%). Anterior protrusions (n = 19) comprised Type I (47.4%), Type II (42.1%), and Type IV (10.5%), whereas lateral protrusions (n = 47) included Type II (51.1%), Type I (40.4%), and Type IV (6.4%). Type IV malar asymmetry was significantly prevalent (P < 0.05). Severe untreated craniofacial deformities may persist by impacting facial structures including the cheeks and jaw. These findings suggest that untreated severe DP in infancy can cause residual facial deformities, thereby highlighting the importance of early intervention to avoid severe distortion.

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Functional non-coding variants in a TTTG microsatellite on chromosome 15q26.1 are a common genetic etiology of congenital hypothyroidism with thyroid gland in situ.

Hirohito Shima, Tomohiro Nakagawa, Kanako Kojima-Ishii, Akinobu Miura, Ikuma Fujiwara, Satoshi Narumi, Atsuo Kikuchi, Junko Kanno

Hormone research in paediatrics    1 - 6 2025

ISSN  16632818

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INTRODUCTION: Variants affecting a microsatellite on the non-coding region of chromosome 15q26.1 are associated with familial non-autoimmune thyroid abnormalities characterized by mild congenital hypothyroidism (CH) with elevated thyroglobulin (Tg) levels. Some individuals who carry these variants may develop multinodular goiter (MNG) if left untreated. Although these variants have been recognized as genetic etiologies of CH, nongoitrous, 3 (CHNG3), the associated severity of CH remains unclear. METHODS: A cohort of 63 participants diagnosed with CH at Tohoku University underwent screening for genetic variants on 15q26.1. We then analyzed the clinical phenotypes of the variant-carrying participants. RESULTS: We identified five 15q26.1 variant carriers from four families among the cohort. Family histories of thyroid abnormalities were documented in three of these five cases. The variant carriers had mild CH phenotypes, with two discontinuing levothyroxine treatment and the others requiring relatively low doses (1.33-1.89 µg/kg/day) at their final visit. During levothyroxine treatment, serum thyroglobulin and thyroid-stimulating hormone (TSH) levels were within the reference ranges at the majority of the evaluation points. Three of the five participants continued treatment into adulthood, whereas the other two discontinued it and maintained serum TSH levels within the reference range. All five participants exhibited normal intellectual development and stature. CONCLUSION: These findings provide further evidence supporting the role of 15q26.1 variants as a common genetic etiology of CH, with clinical phenotypes including transient CH. Early genetic evaluation may facilitate the identification of 15q26.1 variant carriers among patients who are diagnosed with CH.

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Case Report: GATA2 deficiency in two families with novel frameshift variants highlighting phenotypic diversity and need for early diagnosis

Morimoto M., Nishikawa T., Hijikata A., Kasabata H., Maeda N., Kanmura S., Horikawa S., Nagahama J., Nakamura A., Nakamura T., Abematsu T., Nakagawa S., Shimura K., Narumi S., Kanegane H., Okamoto Y.

Frontiers in Immunology 16   1644552 2025

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Background: GATA2 deficiency, a syndrome caused by heterozygous loss-of-function variants in the GATA2 gene, is characterized by immunodeficiency, bone marrow failure, and predisposition to myeloid neoplasms. Its clinical presentation is highly variable, making early diagnosis challenging. Although GATA2 deficiency has been linked to systemic inflammation, gastrointestinal involvement mimicking inflammatory bowel disease (IBD) is extremely rare. Case presentation: This report presented the case of two adolescent boys with no family history of novel heterozygous frameshift GATA2 variants. Notably, Patient 1 initially presented with clinical and endoscopic features strongly suggestive of Crohn’s disease, including weight loss, perianal abscess, and characteristic intestinal ulcers, before developing acute myeloid leukemia with monosomy 7. This is a rare presentation of GATA2 deficiency manifesting initially with Crohn’s disease-like symptoms. Patient 2 presented with intractable cutaneous warts and pancytopenia, later diagnosed as myelodysplastic syndrome with der(1;7)(q10;p10). Both patients harbored novel GATA2 frameshift variants predicted to eliminate the DNA-binding domain, suggesting a loss-of-function mechanism. Conclusion: These cases expand the phenotypic spectrum of GATA2 deficiency and highlight that atypical IBD-like symptoms, including Crohn’s disease-like presentations, may cause an initial manifestation. GATA2 deficiency should be considered in patients with IBD-like symptoms, refractory skin disorders, and hematological abnormalities. Early genetic testing and family screening are essential to ensuring timely diagnosis and curative hematopoietic stem cell transplantation before progression to advanced myeloid disease.

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Establishment of Star-edited Y1 cells as a novel in vitro functional assay for STAR

Takeshi Sato, Satoshi Narumi, Tetsushi Sakuma, Kazuhiro Shimura, Yosuke Ichihashi, Takashi Yamamoto, Tomohiro Ishii, Tomonobu Hasegawa

Journal of Molecular Endocrinology (Bioscientifica)  73 ( 4 )  2024.11

ISSN  09525041

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Genetic variants involving steroidogenic acute regulatory protein cause lipoid congenital adrenal hyperplasia, which is characterized by impaired steroidogenesis in the adrenal glands and gonads. Functional assessment of variant STAR proteins is necessary for accurate genetic diagnosis. Ideally, steroidogenic cells should be used to assess the functionality of STAR proteins, but the presence of endogenous STARs in steroidogenic cells precludes such a method. Here, we generated Star-edited cells from steroidogenic Y1 mouse adrenocortical tumor cells by genome editing. Star-edited Y1 cells exhibited very low but measurable cAMP-dependent pregnenolone production. Furthermore, stimulation of the cAMP pathway for two weeks resulted in the formation of lipid droplets in the cytoplasm of Star-edited Y1 cells, which resembled the histology of the adrenal glands of patients with lipoid congenital adrenal hyperplasia. The steroidogenic defect of Star-edited Y1 cells can be restored by transient over-expression of mouse Star. We found that human STAR can also restore defective steroidogenesis of Star-edited Y1 cells, and were able to construct a novel in vitro system to evaluate human STAR variants. Collectively, we established Star-edited Y1 cells that retain the steroidogenic pathway downstream the Star protein. Star-edited Y1 cells recapitulate the functional and morphological changes of lipoid congenital adrenal hyperplasia, and can be used to evaluate the functionality of human STAR variants.

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Znrf3 exon 2 deletion mice do not recapitulate congenital adrenal hypoplasia.

Noboru Uchida, Tomohiro Ishii, Naoko Amano, Shuji Takada, Kyoko Kobayashi, Tomoaki Murakami, Satoshi Narumi, Tomonobu Hasegawa

Journal of molecular endocrinology 73 ( 4 )  2024.11

ISSN  09525041

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Wnt/β-catenin signaling is essential for adrenocortical development. Zinc and ring finger 3 (ZNRF3), an E3 ubiquitin ligase that attenuates Wnt/β-catenin signaling, is negatively regulated by R-spondin via an extracellular domain that is partially encoded by exon 2 of ZNRF3. We recently identified ZNRF3 exon 2 deletions in three individuals with congenital adrenal hypoplasia. ZNRF3 exon 2 deletion impairs R-spondin binding, thereby attenuating β-catenin expression, eventually developing congenital adrenal hypoplasia. To elucidate the influence of ZNRF3/Znrf3 exon 2 deletion on adrenocortical development, we generated homozygous Znrf3 exon 2 deletion (Znrf3Δ2/Δ2) mice. The adrenal glands of Znrf3Δ2/Δ2 mice did not show gross morphological changes at birth but became enlarged with age. Moderate hyperplasia of the zona fasciculata (ZF), dispersed medulla arrangement, and a radially spreading zone comprised of cells with large nuclei between the ZF and medulla were observed at 6 weeks of age. Immunohistochemistry revealed low levels of 20α-hydroxysteroid dehydrogenase, a marker of the adrenal X-zone, in Znrf3Δ2/Δ2 mice. Plasma ACTH and serum corticosterone levels in Znrf3Δ2/Δ2 mice did not differ significantly from those in wild-type mice. Transcriptome analyses of the adrenal glands revealed substantial downregulation of X-zone markers but no significant changes in the expression of genes involved in the Wnt/β-catenin signaling pathway. These results show that a species-specific difference in the effects of ZNRF3/Znrf3 exon 2 deletions in humans and mice; Znrf3Δ2/Δ2 mice do not develop congenital adrenal hypoplasia but instead exhibit moderate ZF hyperplasia, dispersed medulla arrangement, and X-zone dysplasia.

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Effectiveness of inactivated influenza vaccine in children during the 2023/24 season: The first season after relaxation of intensive COVID-19 measures.

Masayoshi Shinjoh, Mizuki Yaginuma, Yoshio Yamaguchi, Kazuyo Tamura, Munehiro Furuichi, Yuki Tsumura, Ryo Itaki, Asef Iqbal, Naonori Maeda, Atsushi Narabayashi, Akinobu Kamei, Akimichi Shibata, Go Yamada, Mitsuhiro Nishida, Tsunematsu Kenichiro, Michiko Chiga, Motoko Shimoyamada, Makoto Yoshida, Naoya Fukushima, Yuji Nakata, Hiroyuki Fukushima, Chiharu Kawakami, Satoshi Narumi, Norio Sugaya

Vaccine 42 ( 23 ) 126241 - 126241 2024.10

Accepted,  ISSN  0264410X

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BACKGROUND: The annual administration of the influenza vaccine is the most effective method for preventing influenza. We have evaluated the effectiveness of the inactivated influenza vaccine in children aged 6 months to 15 years across the seasons from 2013/2014 to 2022/2023. This study aims to investigate the effectiveness of the inactivated influenza vaccine in the 2023/2024 season, the first year following the easing of strict COVID-19 measures, and possibly the last season when only the inactivated vaccine is available on the market. METHODS: Adjusted vaccine effectiveness for the 2023/2024 season was assessed using a test-negative case-control design, with results based on polymerase chain reaction and rapid influenza diagnostic tests. Vaccine effectiveness was calculated by influenza type and patient hospitalization/outpatient status. RESULTS: A total of 1832 children were recruited. The inactivated influenza vaccine was effective in preventing both symptomatic influenza A and B in both inpatient and outpatient settings. Overall vaccine effectiveness for influenza A was 51% (95% confidence interval [CI], 23%-69%, n = 930) in inpatient settings and 54% (95%CI, 27%-71%, n = 559) in outpatient settings. For influenza B, effectiveness was 60% (95%CI, 22%-79%, n = 859) in inpatient settings and 56% (95%CI, 26%-74%, n = 558) in outpatient settings. Analysis suggested that administering two doses enhanced effectiveness specifically against influenza B. CONCLUSIONS: This is the first study to demonstrate influenza vaccine effectiveness in children after the relaxation of strict COVID-19 measures in Japan (2023/2024). We recommend the current inactivated vaccine for preventing both influenza A and B in children, with consideration for the potential use of two doses to enhance effectiveness against influenza B.

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Digital clubbing without hypoxia for lysinuric protein intolerance

Watanabe D., Tsujioka Y., Nakato D., Yamada M., Suzuki H., Ohnishi T., Tamai N., Kijima T., Takenouchi T., Miya F., Narumi S., Kosaki K.

European Journal of Medical Genetics 71   104967 2024.10

ISSN  17697212

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Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in SLC7A7 and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the SLC7A7, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, HPGD and SLCO2A1. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with SLC7A7 may be attributed to the mechanism of increased PGE2 production.

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Comprehensive study on central precocious puberty: molecular and clinical analyses in 90 patients.

Hiromune Narusawa, Tomoe Ogawa, Hideaki Yagasaki, Keisuke Nagasaki, Tatsuki Urakawa, Tomohiro Saito, Shun Soneda, Saori Kinjo, Shinichiro Sano, Mitsukazu Mamada, Shintaro Terashita, Sumito Dateki, Satoshi Narumi, Yasuhiro Naiki, Reiko Horikawa, Tsutomu Ogata, Maki Fukami, Masayo Kagami

The Journal of clinical endocrinology and metabolism 110 ( 4 ) 1023 - 1036 2024.09

ISSN  0021-972X

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CONTEXT: Defects in MKRN3, DLK1, KISS1, and KISS1R and some disorders, such as Temple syndrome (TS14), cause central precocious puberty (CPP). Recently, pathogenic variants (PVs) in MECP2 have been reported to be associated with CPP. OBJECTIVE: We aimed to clarify the contribution of (epi)genetic abnormalities to CPP and clinical and hormonal features in each etiology. SUBJECTS AND METHODS: We conducted targeted sequencing for MKRN3, DLK1, MECP2, KISS1, and KISS1R and methylation analysis for screening of imprinting disorders such as TS14 associated with CPP in 90 patients with CPP (no history of brain injuries and negative brain MRI) and collected their clinical and laboratory data. We measured serum DLK1 levels in three patients with TS14 and serum MKRN3 levels in two patients with MKRN3 genetic defects, together with some etiology-unknown patients with CPP and controls. RESULTS: We detected eight patients with TS14 (six, epimutation; one, mosaic maternal uniparental disomy chromosome 14; one, microdeletion) and three patients with MKRN3 genetic defects (one, PV; one, 13-bp deletion in the 5'-untranslated region (5'-UTR); one, microdeletion) with family histories of paternal early puberty. There were no patients with PVs identified in MECP2, KISS1, or KISS1R. We confirmed low serum MKRN3 level in the patient with a deletion in 5'-UTR. The median height at initial evaluation of TS14 patients was lower than that of all patients. Six patients with TS14 were born small for gestational age (SGA). CONCLUSION: (Epi)genetic causes were identified in 12.2% of patients with CPP at our center. For patients with CPP born SGA or together with family histories of paternal early puberty, (epi)genetic testing for TS14 and MKRN3 genetic defects should be considered. (271/250).

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Genotype-Phenotype Correlations in Thirty Japanese Patients with Congenital Hypothyroidism Attributable to TG Defects.

Kanako Tanase-Nakao, Megumi Iwahashi-Odano, Chiho Sugisawa, Kiyomi Abe, Koji Muroya, Yukiyo Yamamoto, Yasusada Kawada, Yuichi Mushimoto, Kazuhiro Ohkubo, Saori Kinjo, Kazuhiro Shimura, Kohei Aoyama, Haruo Mizuno, Tomoyuki Hotsubo, Chie Takahashi, Tsuyoshi Isojima, Yoko Kina, Satoshi Takakuwa, Junpei Hamada, Miwa Sawaki, Keiichi Shigehara, Satoru Sugimoto, Yuri Etani, Hiroko Narumi-Wakayama, Yusuke Mine, Tomonobu Hasegawa, Akira Hishinuma, Satoshi Narumi

The Journal of clinical endocrinology and metabolism 109 ( 9 ) 2358 - 2365 2024.09

ISSN  0021972X

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CONTEXT: Thyroglobulin (Tg), encoded by TG, is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS). OBJECTIVE: We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period. SUBJECTS AND METHODS: We screened 1061 patients with CH for thirteen CH-related genes and identified thirty patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into two groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the seven missense variants using HEK293 cells. RESULTS: Twenty-seven rare TG variants were detected, including fifteen nonsense, three frameshift, two splice-site, and seven missense variants. Patients were divided into two groups: thirteen patients with biallelic truncating variants and seventeen patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with TSH stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the seven missense variants was confirmed in vitro. CONCLUSION: To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement.

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Molecular and Clinical Features of Congenital Hypothyroidism Due to Multiple DUOX2 Variants.

Erika Uehara, Kiyomi Abe, Kanako Tanase-Nakao, Koji Muroya, Atsushi Hattori, Keiko Matsubara, Maki Fukami, Satoshi Narumi

Thyroid : official journal of the American Thyroid Association 34 ( 7 ) 827 - 836 2024.07

ISSN  10507256

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Background: DUOX2 is one of the major causative genes of congenital hypothyroidism (CH). Still, the mutation spectrum and clinical outcomes of biallelic DUOX2 variants are not fully understood. This study aimed to elucidate the molecular features and long-term clinical manifestations of CH caused by multiple pathogenic DUOX2 variants. Methods: A total of 255 patients with CH were screened for rare variants of 11 known causative genes. DUOX2 variants were classified according to their protein structure and residual activity. In vitro assays were performed for several variants of unknown functions. Clinical analyses were conducted for patients with multiple pathogenic variants of DUOX2 but not of other genes. Results: We identified 24 pathogenic variants of DUOX2, together with two benign variants and seven variants of uncertain significance, in 63 patients. The pathogenic variants included three missense substitutions and one frameshift variant that have not yet been linked to CH. Twenty-one patients carried multiple pathogenic DUOX2 variants without any other pathogenic gene variants. Three of the 21 patients harbored homozygous variants. Family analysis, long-read amplicon sequencing, and haplotype phasing confirmed compound heterozygosity of the DUOX2 variants in 14 patients, whereas the allelic positions of the variants in the remaining four patients could not be determined. Of the 21 patients, 19 were treated with levothyroxine; their ages at drug withdrawal ranged from 9 months to 21.4 years. Three patients required retreatment after drug-free intervals of 6 months, 8 months, and 10 years. There were no differences in clinical severity among patients with DUOX2 amorphic/amorphic, amorphic/hypomorphic, and hypomorphic/hypomorphic variants. Conclusions: These results broaden the mutational spectrum of DUOX2. Furthermore, our data imply that patients with multiple pathogenic DUOX2 variants typically exhibit transient CH without significant genotype-phenotype correlations. Most importantly, this study demonstrated for the first time that these patients are at risk of developing recurrent hypothyroidism after a long drug-free interval.

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15q26.1マイクロサテライトリピート数減少による家族性甲状腺異常症の5家系の新生児期の特徴

丸尾 良浩, 塚村 篤史, 筒井 英美, 長井 静世, 長崎 啓祐, 鳴海 覚志

日本マス・スクリーニング学会誌 ((一社)日本マススクリーニング学会)  34 ( 2 ) 234 - 234 2024.07

ISSN  0917-3803

Disulfide bonds of thyroid peroxidase are critical elements for subcellular localization, proteasome-dependent degradation, and enzyme activity

Hajime Iwasaki, Hirotsugu Suwanai, Fumiyoshi Yakou, Hiroyuki Sakai, Keitaro Ishii, Natsuko Hara, Ashley M. Buckle, Kohsuke Kanekura, Tamami Miyagi, Satoshi Narumi, Ryo Suzuki

Thyroid® (Mary Ann Liebert Inc)  34 ( 5 ) 659 - 667 2024.05

ISSN  10507256

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Background: Congenital hypothyroidism (CH) is caused by mutations in cysteine residues, including Cys655 and Cys825 that form disulfide bonds in thyroid peroxidase (TPO). It is highly likely that these disulfide bonds could play an important role in TPO activity. However, to date, no study has comprehensively analyzed cysteine mutations that form disulfide bonds in TPO. In this study, we induced mutations in cysteine residues involved in disulfide bonds formation and analyzed their effect on subcellular localization, degradation, and enzyme activities to evaluate the importance of disulfide bonds in TPO activity. Methods: Vector plasmid TPO mutants, C655F and C825R, known to occur in CH, were transfected into HEK293 cells. TPO activity and protein expression levels were measured by the Amplex red assay and Western blotting. The same procedure was performed in the presence of MG132 proteasome inhibitor. Subcellular localization was determined using immunocytochemistry and flow cytometry. The locations of all disulfide bonds within TPO were predicted using in silico analysis. All TPO mutations associated with disulfide bonds were induced. TPO activity and protein expression levels were also measured in all TPO mutants associated with disulfide bonds using the Amplex red assay and Western blotting. Results: C655F and C825R showed significantly decreased activity and protein expression compared with the wild type (WT) (p < 0.05). In the presence of the MG132 proteasome inhibitor, the protein expression level of TPO increased to a level comparable with that of the WT without increases in its activity. The degree of subcellular distribution of TPO to the cell surface in the mutants was lower compared with the WT TPO. Twenty-four cysteine residues were involved in the formation of 12 disulfide bonds in TPO. All TPO mutants harboring an amino acid substitution in each cysteine showed significantly reduced TPO activity and protein expression levels. Furthermore, the differences in TPO activity depended on the position of the disulfide bond. Conclusions: All 12 disulfide bonds play an important role in the activity of TPO. Furthermore, the mutations lead to misfolding, degradation, and membrane insertion.

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4世代にわたり特異的甲状腺表現型を示した家系とその病因PAX8新規バリアントG56Sの多階層的機能解析

阿部 清美, 西岡 淳子, 小田野 めぐみ, 岩野 麗子, 藏本 純子, 鳴海 覚志, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 1 ) 294 - 294 2024.05

ISSN  0029-0661

Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities.

Satoshi Narumi, Keisuke Nagasaki, Mitsuo Kiriya, Erika Uehara, Kazuhisa Akiba, Kanako Tanase-Nakao, Kazuhiro Shimura, Kiyomi Abe, Chiho Sugisawa, Tomohiro Ishii, Kenichi Miyako, Yukihiro Hasegawa, Yoshihiro Maruo, Koji Muroya, Natsuko Watanabe, Eijun Nishihara, Yuka Ito, Takahiko Kogai, Kaori Kameyama, Kazuhiko Nakabayashi, Kenichiro Hata, Maki Fukami, Hirohito Shima, Atsuo Kikuchi, Jun Takayama, Gen Tamiya, Tomonobu Hasegawa

Nature genetics 56 ( 5 ) 869 - 876 2024.05

ISSN  10614036

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Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.

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中枢性思春期早発症患者90症例の遺伝学的解析と臨床像の検討

成澤 宏宗, 浦川 立貴, 長崎 啓祐, 矢ヶ崎 英晃, 内木 康博, 佐野 伸一朗, 齋藤 朋洋, 曽根田 瞬, 鳴海 覚志, 堀川 玲子, 緒方 勤, 深見 真紀, 鏡 雅代

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 1 ) 355 - 355 2024.05

ISSN  0029-0661

Letter to the Editor regarding “Serum steroid metabolite profiling by LC-MS/MS in two phenotypic male patients with HSD17B3 deficiency: Implications for hormonal diagnosis”

Takeshi Sato, Satsuki Nakano, Misa Honda, Satoshi Narumi, Tomohiro Ishii, Tomonobu Hasegawa

The Journal of Steroid Biochemistry and Molecular Biology (Elsevier BV)  239   106484 - 106484 2024.05

ISSN  09600760

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日本人若年発症原発性アルドステロン症の遺伝学的・臨床的特徴

内田 登, 石井 智弘, 西本 紘嗣郎, 小原 收, 鳴海 覚志, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 1 ) 323 - 323 2024.05

ISSN  0029-0661