2024/06/22 更新

写真a

ニユウヅキ ヒロミ
入月 浩美
NIYUZUKI Hiromi
所属
医歯学総合病院 ゲノム医療部 遺伝医療センター 助教
職名
助教
外部リンク

学位

  • 博士(医学) ( 1997年3月   新潟大学 )

経歴

  • 新潟大学   医歯学総合病院 ゲノム医療部 遺伝医療センター   助教

    2021年4月 - 現在

 

論文

  • Phenotypic and genetic spectra of galactose mutarotase deficiency: A nationwide survey conducted in Japan

    Yasuko Mikami-Saito, Yoichi Wada, Natsuko Arai-Ichinoi, Yoko Nakajima, Sayaka Suzuki-Ajihara, Kei Murayama, Toju Tanaka, Chikahiko Numakura, Takashi Hamazaki, Noboru Igarashi, Hiroyuki Esaki, Reiko Kagawa, Tomotaka Kono, Takaaki Sawada, Tomo Sawada, Hiromi Nyuzuki, Hiroki Hirai, Seiko Fumoto, Junko Matsuda, Ayako Matsunaga, Shinsuke Maruyama, Kenichiro Yamaguchi, Miwa Yoshino, Eriko Totsune, Atsuo Kikuchi, Toshihiro Ohura, Shigeo Kure

    Genetics in Medicine   101165 - 101165   2024年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.gim.2024.101165

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  • Hypocarnitinemia in twins after maternal pivalate-conjugated antibiotic therapy. 国際誌

    Takuya Fuse, Yuta Aizawa, Hiromi Nyuzuki, Kentaro Sawano, Keisuke Nagasaki, Akihiko Saitoh

    Pediatrics international : official journal of the Japan Pediatric Society   66 ( 1 )   e15750   2024年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/ped.15750

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  • GPATCH4 contributes to nucleolus morphology and its dysfunction impairs cell viability. 国際誌

    Kazuki Kodera, Ryuichi Hishida, Akiko Sakai, Hiromi Nyuzuki, Noriko Matsui, Tomoyuki Yamanaka, Akihiko Saitoh, Hideaki Matsui

    Biochemical and biophysical research communications   693   149384 - 149384   2023年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The nucleolus serves a multifaceted role encompassing not only rRNA transcription and ribosome synthesis, but also the intricate orchestration of cell cycle regulation and the modulation of cellular senescence. G-patch domain containing 4 (GPATCH4) stands as one among the nucleolar proteins; however, its functional significances remain still unclear. In order to elucidate the functions of GPATCH4, we examined the effects of its dysfunction on cellular proliferation, alterations in nucleolar architecture, apoptotic events, and cellular senescence. Through experimentation conducted on cultured neuroblastoma SH-SY5Y cells, the reduction of GPATCH4 caused inhibition of cellular proliferation, concurrently fostering escalated apoptotic susceptibilities upon exposure to high-dose etoposide. In the realm of nucleolar morphology comparisons, a discernible decline was noted in the count of nucleoli per nucleus, concomitant with a significant expansion in the area occupied by individual nucleoli. Upon induction of senescence prompted by low-dose etoposide, GPATCH4 knockdown resulted in decreased cell viability and increased expression of senescence-associated markers, namely senescence-associated β-galactosidase (SA-β-GAL) and p16. Furthermore, GPATCH4 dysfunction elicited alterations in the gene expression profile of the ribosomal system. In sum, our findings showed that GPATCH4 is a pivotal nucleolar protein that regulates nucleolar morphology and is correlated with cell viability.

    DOI: 10.1016/j.bbrc.2023.149384

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  • A Study of Maternal Patients Diagnosed with Inborn Errors of Metabolism Due to Positive Newborn Mass Screening in Their Newborns. 国際誌

    Takanori Onuki, Shota Hiroshima, Kentaro Sawano, Nao Shibata, Yohei Ogawa, Keisuke Nagasaki, Hiromi Nyuzuki

    Children (Basel, Switzerland)   10 ( 8 )   2023年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: There are reports of mothers being diagnosed with inborn errors of metabolism (IEM) via positive newborn screening (NBS) of their newborns. Mothers with IEM are often considered to have mild cases of little pathological significance. Based in Niigata Prefecture, this study aimed to investigate mothers newly diagnosed with IEM via positive NBS in their newborns using tandem mass spectrometry, and to clarify the disease frequency and severity. METHODS: This was a single-institution, population-based, retrospective study. The subjects were mothers whose newborns had false-positive NBS, among 80,410 newborns who underwent NBS between April 2016 and May 2021. RESULT: there were 3 new mothers were diagnosed with IEM (2 with primary systemic carnitine deficiency (PCD) and 1 with 3-methylcrotonyl-CoA carboxylase deficiency) out of 5 who underwent examination among 18 false positives. The opportunity for diagnosis was low C0 and high C5-OH acylcarnitine levels in their newborn. Two novel SLC22A5 variants (c.1063T > C/c.1266A > G) were identified in patients with PCD. None of the patients had any complications at the time of diagnosis, but two patients showed improvement in fatigue and headache after taking oral carnitine. CONCLUSION: New mothers with IEM cannot be considered as mild cases and need to be treated when necessary. The two novel SLC22A5 variants further expand the variant spectrum of PCD.

    DOI: 10.3390/children10081341

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  • Peripheral precocious puberty in a girl with an intracranial hCG-producing tumor: case report and literature review.

    Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Masayasu Okada, Keisuke Nagasaki

    Endocrine journal   68 ( 12 )   1463 - 1467   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human chorionic gonadotropin (hCG)-producing tumors cause peripheral precocious puberty (PP) in boys, but generally not in girls. Homology between LH and hCG activates the LH receptor in testicular Leydig cells, increases testosterone production, and causes virilization. However, since FSH action is required for follicle development, hCG action alone does not increase estradiol (E2) production and does not cause feminization. Only a few cases of peripheral PP with hCG tumors in girls have been reported. We describe the case of a 7-year-old Japanese girl with peripheral PP associated with an hCG-producing tumor. She had prolonged vomiting, loss of appetite, and Tanner stage III breast development. Although no apparent increase in growth rate, bone age was advanced at 9.8 years. Serum E2 was slightly elevated and LH and FSH were below the measurement sensitivity, and abdominal ultrasonography and computed tomography images showed no abnormal findings in the uterus or ovaries. Subsequently, she developed visual field disturbance and loss of consciousness, and brain magnetic resonance imaging revealed an intracranial tumor. Based on pathological findings and abnormally high serum hCG-β level (48,800 IU/L), intracranial choriocarcinoma was diagnosed. 2.5 months after the start of chemotherapy, the hCG-β level became almost negative and the breast development disappeared synchronously. Tissue immunostaining of the tumor showed strong positivity for aromatase and hCG, indicating that the choriocarcinoma cells themselves may have produced estrogen via aromatase. This unique case highlights the possibility that hCG-producing tumors can cause peripheral PP in girls as well as boys.

    DOI: 10.1507/endocrj.EJ21-0117

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  • A case of adolescent trichorhinophalangeal syndrome undergoing pelvic osteotomy for bilateral acetabular dysplasia.

    Kentaro Sawano, Hiromi Nyuzuki, Keisuke Nagasaki, Hayato Suzuki, Ken Suda, Dai Miyasaka, Norio Imai, Akihiko Saitoh

    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association   2021年9月

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  • Re-Evaluation of the Prevalence of Permanent Congenital Hypothyroidism in Niigata, Japan: A Retrospective Study. 国際誌

    Keisuke Nagasaki, Hidetoshi Sato, Sunao Sasaki, Hiromi Nyuzuki, Nao Shibata, Kentaro Sawano, Shota Hiroshima, Tadashi Asami

    International journal of neonatal screening   7 ( 2 )   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although newborn screening (NBS) for congenital hypothyroidism (CH) in Japan started more than 40 years ago, the prevalence of CH remains unclear. Prevalence estimations among NBS-positive CH individuals include those with transient hypothyroidism and transient hyperthyrotropinemia, and re-evaluation with increasing age is necessary to clarify the actual incidence. Thus, we re-evaluated the incidence of permanent CH. Of the 106,114 patients who underwent NBS in the Niigata Prefecture, Japan, between April 2002 and March 2006, 116 were examined further due to high thyroid-stimulating hormone levels (>8 mIU/L) and were included in the study. We retrospectively evaluated their levothyroxine sodium (LT4) replacement therapy status from the first visit to 15 years of age. Of the 116 NBS-positive patients, 105 (91%) were initially examined in our department. Of these, 72 (69%) started LT4 replacement therapy on the first visit. Subsequently, 27 patients continued LT4 replacement until 15 years of age after multiple re-evaluations. The prevalence of permanent CH in the Niigata Prefecture during this period was 1 in 2500-3500 children. Ultimately, 62.5% of patients on LT4 replacement discontinued treatment by 15 years of age. This is the first study to clarify the true prevalence of permanent CH in Japan.

    DOI: 10.3390/ijns7020027

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  • Regulation of Serum Sodium Levels during Chemotherapy Using Selective Arginine Vasopressin V2-Receptor Antagonist Tolvaptan in a Four-Year-Old Girl with a Suprasellar Germ Cell Tumor. 国際誌

    Shota Hiroshima, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Keisuke Nagasaki

    Children (Basel, Switzerland)   8 ( 4 )   2021年4月

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    記述言語:英語  

    There are limited reports on the use of tolvaptan for syndrome of inappropriate antidiuretic hormone secretion (SIADH) in children. Managing serum sodium levels in SIADH patients during chemotherapy is often difficult because of the need for massive fluid infusions. We report the course of the use of tolvaptan for the treatment of hyponatremia during chemotherapy in a four-year-old girl with a suprasellar germ cell tumor. The patient was a Japanese girl who presented with left ptosis with a mass in the pituitary gland and cavernous sinus. She was diagnosed with an intermediate-grade germ cell tumor and was treated with carboplatin and etoposide combination chemotherapy. She developed hyponatremia due to SIADH caused by intravenous infusion therapy before chemotherapy. Subsequently, tolvaptan (3.25 mg; 0.20 mg/kg/dose) was administered orally to control serum sodium levels. After 4 h of administration, a marked increase in urine volume of up to 15 mL/kg/h was observed, and serum sodium level increased from 126 to 138 mEq/L after 10 h of tolvaptan administration, followed by a decrease in urine volume. The use of tolvaptan in pediatric patients with SIADH who require intravenous hydration during chemotherapy can be useful for the management of serum sodium balance.

    DOI: 10.3390/children8040293

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  • Degeneration of dopaminergic neurons and impaired intracellular trafficking in Atp13a2 deficient zebrafish. 国際誌

    Hiromi Nyuzuki, Shinji Ito, Keisuke Nagasaki, Yohei Nitta, Noriko Matsui, Akihiko Saitoh, Hideaki Matsui

    IBRO reports   9   1 - 8   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    ATP13A2 is the autosomal recessive causative gene for juvenile-onset Parkinson's disease (PARK9, Parkinson's disease 9), also known as Kufor-Rakeb syndrome. The disease is characterized by levodopa-responsive Parkinsonism, supranuclear gaze palsy, spasticity, and dementia. Previously, we have reported that Atp13a2 deficient medaka fish showed dopaminergic neurodegeneration and lysosomal dysfunction, indicating that lysosome-autophagy impairment might be one of the key pathogeneses of Parkinson's disease. Here, we established Atp13a2 deficient zebrafish using CRISPR/Cas9 gene editing. We found that the number of TH + neurons in the posterior tuberculum and the locus coeruleus significantly reduced (dopaminergic neurons, 64 % at 4 months and 37 % at 12 months, p < 0.001 and p < 0.05, respectively; norepinephrine neurons, 52 % at 4 months and 40 % at 12 months, p < 0.001 and p < 0.05, respectively) in Atp13a2 deficient zebrafish, proving the degeneration of dopaminergic neurons. In addition, we found the reduction (60 %, p < 0.05) of cathepsin D protein expression in Atp13a2 deficient zebrafish using immunoblot. Transmission electron microscopy analysis using middle diencephalon samples from Atp13a2 deficient zebrafish showed lysosome-like bodies with vesicle accumulation and fingerprint-like structures, suggesting lysosomal dysfunction. Furthermore, a significant reduction (p < 0.001) in protein expression annotated with vesicle fusion with Golgi apparatus in Atp13a2 deficient zebrafish by liquid-chromatography tandem mass spectrometry suggested intracellular trafficking impairment. Therefore, we concluded that Atp13a2 deficient zebrafish exhibited degeneration of dopaminergic neurons, lysosomal dysfunction and the possibility of intracellular trafficking impairment, which would be the key pathogenic mechanism underlying Parkinson's disease.

    DOI: 10.1016/j.ibror.2020.05.002

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  • Correction: Biallelic GALM pathogenic variants cause a novel type of galactosemia. 国際誌

    Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

    Genetics in medicine : official journal of the American College of Medical Genetics   22 ( 7 )   1281 - 1281   2020年7月

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    記述言語:英語  

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    DOI: 10.1038/s41436-020-0836-z

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  • Ski3/TTC37 deficiency associated with trichohepatoenteric syndrome causes mitochondrial dysfunction in Drosophila. 国際誌

    Kohei Ohnuma, Yoshihito Kishita, Hiromi Nyuzuki, Masakazu Kohda, Yuta Ohtsu, Satomi Takeo, Tsunaki Asano, Yukiko Sato-Miyata, Akira Ohtake, Kei Murayama, Yasushi Okazaki, Toshiro Aigaki

    FEBS letters   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tetratricopeptide repeat protein 37 (TTC37) is a causative gene of trichohepatoenteric syndrome (THES). However, little is known about the pathogenesis of this disease. Here, we characterize the phenotype of a Drosophila model in which ski3, a homolog of TTC37, is disrupted. The mutant flies are pupal lethal, and the pupal lethality is partially rescued by transgenic expression of wild-type ski3 or human TTC37. The mutant larvae show growth retardation, heart arrhythmia, triacylglycerol accumulation, and aberrant metabolism of glycolysis and the TCA cycle. Moreover, mitochondrial membrane potential and respiratory chain complex activities are significantly reduced in the mutants. Our results demonstrate that ski3 deficiency causes mitochondrial dysfunction, which may underlie the pathogenesis of THES.

    DOI: 10.1002/1873-3468.13792

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  • Timing of hyponatremia development in patients with salt-wasting-type 21-hydroxylase deficiency.

    Rohi Shima, Kentaro Sawano, Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Hidetoshi Sato, Yohei Ogawa, Yuki Abe, Keisuke Nagasaki, Akihiko Saitoh

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology   29 ( 3 )   105 - 110   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10-14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.

    DOI: 10.1297/cpe.29.105

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  • A Japanese Family with DICER1 Syndrome Found in Childhood-Onset Multinodular Goitre. 国際誌

    Keisuke Nagasaki, Nao Shibata, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Satoshi Soda, Takahiko Kogai, Akira Hishinuma

    Hormone research in paediatrics   93 ( 7-8 )   477 - 482   2020年

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    記述言語:英語  

    INTRODUCTION: Germline DICER1 mutations have recently been identified in familial multinodular goitre (MNG). The natural history of thyroid nodules in DICER1 carriers in children is unclear. The purpose of this study was to describe the clinical and genetic findings of childhood-onset MNG with DICER1 carrier in a patient who underwent total thyroidectomy. CASE PRESENTATION: The 6-year-old proband had a thyroid nodule, and the number and size of nodules increased over 3 years. A total thyroidectomy was chosen because of the rapid rise in thyroglobulin levels, discomfort when swallowing, and the mother's history of poorly differentiated thyroid cancer (PDTC). Histopathology revealed adenomatous goitre without malignant cells. Her mother, maternal aunt, and maternal grandmother also had thyroid nodules removed during adolescence. Also, her mother had PDTC with lung metastases, and her maternal aunt had an ovarian germ cell tumour. DICER1 mutation analysis identified a heterozygous novel nonsense mutation (c.4509C>G, p.Y1503X) for the patient, her mother, her maternal grandmother, and her asymptomatic elder brother. Y1503X was identified in all resected thyroid tissues, while heterozygous D1709G, D1810V, and E1813K mutations were identified in individual nodules. DISCUSSION/CONCLUSION: A thyroid nodule was detected in chemotherapy- or radiotherapy-naïve patient with DICER1 carrier aged 6 years, and MNG developed over 3 years. This pedigree highlights the natural history of nodular disease in DICER1 carriers and identifies a possible association between DICER1 and more aggressive malignancies.

    DOI: 10.1159/000511140

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  • First Japanese case of maternal phenylketonuria treated with sapropterin dihydrochloride and the normal growth and development of the child. 国際誌

    Hiromi Nyuzuki, Taro Yamazaki, Megumi Saito, Akira Ohtake

    Molecular genetics and metabolism reports   21   100526 - 100526   2019年12月

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    記述言語:英語  

    Sapropterin dihydrochloride (SD) may be a new treatment option for women with phenylketonuria (PKU) who plan to become pregnant. We report the first Japanese case of maternal PKU treated with SD. The patient was administered SD at 10-20 mg/kg/day, which increased phenylalanine tolerance during the pregnancy and lactation. No adverse events occurred, and she delivered a healthy neonate. Normal growth and development of the child confirms the efficacy and safety of SD.

    DOI: 10.1016/j.ymgmr.2019.100526

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  • 新生児マススクリーニングを契機に発見した遺伝性ガラクトース血IV型の2例

    入月 浩美, 和田 陽一, 市野井 那津子, 菊池 敦生, 小川 洋平, 長崎 啓祐, 呉 繁夫

    日本先天代謝異常学会雑誌   35   186 - 186   2019年9月

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    記述言語:日本語   出版者・発行元:日本先天代謝異常学会  

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  • Biallelic GALM pathogenic variants cause a novel type of galactosemia. 国際誌

    Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

    Genetics in medicine : official journal of the American College of Medical Genetics   21 ( 6 )   1286 - 1294   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. METHODS: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. RESULTS: The highest blood galactose levels observed in each patient were 17.3-41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients' peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. CONCLUSION: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

    DOI: 10.1038/s41436-018-0340-x

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  • 正常子宮サイズと女性外性器を有する45,X/47,XYY核型のTurner症候群

    丸山 馨, 入月 浩美, 佐々木 直, 小川 洋平, 長崎 啓祐, 齋藤 昭彦

    日本小児科学会雑誌   122 ( 12 )   1850 - 1854   2018年12月

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    記述言語:日本語   出版者・発行元:(公社)日本小児科学会  

    5歳女児。低身長の精査目的で当科へ紹介となった。初診時、低身長(-2.2SD)、第5指爪低形成を認めたが、外性器は正常女性型であり、腹部超音波やMRI検査にても子宮サイズは年齢相当であった。血液検査でFSHの上昇を認め、染色体検査結果から45,X[8]/47,XYY[12]核型のTurner症候群による低身長、卵巣機能不全と診断された。本症例はY成分を有する核型であり、性腺の悪性化の可能性があるため両側性腺摘出術を行った。摘出した性腺は両側ともに索状性腺で、悪性化の所見は認めず、また頬粘膜および性腺の性染色体の構成は45,X細胞系列が優位であった。

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  • Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes. 国際誌

    Keisuke Nagasaki, Gen Nishimura, Toru Kikuchi, Hiromi Nyuzuki, Sunao Sasaki, Yohei Ogawa, Akihiko Saitoh

    American journal of medical genetics. Part A   176 ( 3 )   739 - 742   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Omodysplasia-2 (OMOD2; OMIM%16475) is a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies. This clinical phenotype overlaps with that of AD type Robinow syndrome. Recently, a mutation in FZD2 encoding a Frizzled Class Receptor 2 has been identified in a family with AD omodysplasia (an affected girl and her affected mother). Here, we present the second report on a heterozygous novel nonsense FZD2 mutation in OMOD2 or Robinow syndrome-like phenotype. The proband was a 16-year-old boy, who has been followed from infancy to adolescence. He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia. Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends, mildly broad femora, thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals. The abnormal skeletal pattern was persistent in adolescence; however, the humeri and femora became less undermodeled, while the humeri and radii became mildly bowed. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*). The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. Further molecular studies will permit better clarification of the phenotypic spectrum in patients with OMOD2.

    DOI: 10.1002/ajmg.a.38623

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  • PTEN mutation in a Japanese boy with autonomously functioning thyroid nodule. 国際誌

    Hiromi Nyuzuki, Takahiko Kogai, Akira Hishinuma, Yohei Ogawa, Akihiko Saitoh, Keisuke Nagasaki

    Pediatrics international : official journal of the Japan Pediatric Society   59 ( 11 )   1223 - 1224   2017年11月

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    記述言語:英語  

    DOI: 10.1111/ped.13427

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  • Continuous hypomethylation of the KCNQ1OT1:TSS-DMR in monochorionic twins discordant for Beckwith-Wiedemann syndrome. 国際誌

    Takanobu Inoue, Akie Nakamura, Keiko Matsubara, Hiromi Nyuzuki, Keisuke Nagasaki, Akira Oka, Maki Fukami, Masayo Kagami

    American journal of medical genetics. Part A   173 ( 10 )   2847 - 2850   2017年10月

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    記述言語:英語  

    DOI: 10.1002/ajmg.a.38419

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  • A novel mutation in TAZ causes mitochondrial respiratory chain disorder without cardiomyopathy. 国際誌

    Nurun N Borna, Yoshihito Kishita, Kaori Ishikawa, Kazuto Nakada, Jun-Ichi Hayashi, Yoshimi Tokuzawa, Masakazu Kohda, Hiromi Nyuzuki, Yzumi Yamashita-Sugahara, Takashi Nasu, Atsuhito Takeda, Kei Murayama, Akira Ohtake, Yasushi Okazaki

    Journal of human genetics   62 ( 5 )   539 - 547   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tafazzin, encoded by the TAZ gene, is a mitochondrial membrane-associated protein that remodels cardiolipin (CL), an important mitochondrial phospholipid. TAZ mutations are associated with Barth syndrome (BTHS). BTHS is an X-linked multisystemic disorder affecting usually male patients. Through sequence analysis of TAZ, we found one novel mutation c.39_60del p.(Pro14Alafs*19) by whole-exome sequencing and a reported missense mutation c.280C>T p.(Arg94Cys) by Sanger sequencing in two male patients (Pt1 and Pt2). Patient with c.280C>T mutation had dilated cardiomyopathy, while another patient with c.39_60del mutation had no feature of cardiomyopathy. A reported m.1555A>G homoplasmic variant was also identified in the patient having mutation c.39_60del by whole mitochondrial DNA sequencing method. This variant was not considered to be the main cause of mitochondrial dysfunction based on a cytoplasmic hybrid (cybrid) assay. Tafazzin expression was absent in both patient-derived fibroblast cells. Complementation of TAZ expression in fibroblasts from the patient with the novel mutation c.39_60del restored mitochondrial respiratory complex assembly. High-performance liquid chromatography-tandem mass spectrometry-based metabolic analysis revealed the decline of CL and the accumulation of monolysocardiolipin, indicating the loss of tafazzin activity. Owing to phenotypic variability, it is difficult to diagnose BTHS based on clinical features only. We conclude that genetic analysis should be performed to avoid underdiagnosis of this potentially life-threatening inborn error of metabolism.

    DOI: 10.1038/jhg.2016.165

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  • Criteria for radiologic diagnosis of hypochondroplasia in neonates. 国際誌

    Tomoko Saito, Keisuke Nagasaki, Gen Nishimura, Masaki Wada, Hiromi Nyuzuki, Masaki Takagi, Tomonobu Hasegawa, Naoko Amano, Jun Murotsuki, Hideaki Sawai, Takahiro Yamada, Shuhei Sato, Akihiko Saitoh

    Pediatric radiology   46 ( 4 )   513 - 8   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: A radiologic diagnosis of hypochondroplasia is hampered by the absence of age-dependent radiologic criteria, particularly in the neonatal period. OBJECTIVE: To establish radiologic criteria and scoring system for identifying neonates with fibroblast growth factor receptor 3 (FGFR3)-associated hypochondroplasia. MATERIALS AND METHODS: This retrospective study included 7 hypochondroplastic neonates and 30 controls. All subjects underwent radiologic examination within 28 days after birth. We evaluated parameters reflecting the presence of (1) short ilia, (2) squared ilia, (3) short greater sciatic notch, (4) horizontal acetabula, (5) short femora, (6) broad femora, (7) metaphyseal flaring, (8) lumbosacral interpedicular distance narrowing and (9) ovoid radiolucency of the proximal femora. RESULTS: Only parameters 1, 3, 4, 5 and 6 were statistically different between the two groups. Parameters 3, 5 and 6 did not overlap between the groups, while parameters 1 and 4 did. Based on these results, we propose a scoring system for hypochondroplasia. Two major criteria (parameters 3 and 6) were assigned scores of 2, whereas 4 minor criteria (parameters 1, 4, 5 and 9) were assigned scores of 1. All neonates with hypochondroplasia in our material scored ≥6. CONCLUSION: Our set of diagnostic radiologic criteria might be useful for early identification of hypochondroplastic neonates.

    DOI: 10.1007/s00247-015-3518-2

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  • A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. 国際誌

    Masakazu Kohda, Yoshimi Tokuzawa, Yoshihito Kishita, Hiromi Nyuzuki, Yohsuke Moriyama, Yosuke Mizuno, Tomoko Hirata, Yukiko Yatsuka, Yzumi Yamashita-Sugahara, Yutaka Nakachi, Hidemasa Kato, Akihiko Okuda, Shunsuke Tamaru, Nurun Nahar Borna, Kengo Banshoya, Toshiro Aigaki, Yukiko Sato-Miyata, Kohei Ohnuma, Tsutomu Suzuki, Asuteka Nagao, Hazuki Maehata, Fumihiko Matsuda, Koichiro Higasa, Masao Nagasaki, Jun Yasuda, Masayuki Yamamoto, Takuya Fushimi, Masaru Shimura, Keiko Kaiho-Ichimoto, Hiroko Harashima, Taro Yamazaki, Masato Mori, Kei Murayama, Akira Ohtake, Yasushi Okazaki

    PLoS genetics   12 ( 1 )   e1005679   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.

    DOI: 10.1371/journal.pgen.1005679

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  • 低身長を契機に診断された新規変異を認めるIGSF1異常症の一男児例

    佐藤 温洋, 冨田 雄一郎, 深見 真紀, 入月 浩美, 長崎 啓祐

    日本内分泌学会雑誌   91 ( 1 )   316 - 316   2015年4月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • VHL遺伝子変異が同定された家族性褐色細胞腫の小児例

    吉成 裕紀, 長崎 啓祐, 入月 浩美, 佐藤 英利, 小川 洋平, 菊池 透, 齋藤 昭彦

    小児科臨床   68 ( 1 )   125 - 130   2015年1月

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    記述言語:日本語   出版者・発行元:(株)日本小児医事出版社  

    近年、遺伝性褐色細胞腫の原因遺伝子が、さまざま報告されている。VHLは、von Hippel-Lindau病(VHL病)の原因遺伝子であり、その変異により遺伝性褐色細胞腫のほか、血管腫、腎細胞癌、膵嚢胞などを発症する。症例は6歳男児。2年前から続く多汗、体重増加不良、高血圧を主訴に受診した。父親が11歳時に褐色細胞腫の手術を受けていた。初診時、血圧204/148mmHg、尿中ノルアドレナリン高値、腹部MRIで右副腎にT1低信号、T2高信号の35×30mm大の腫瘤性病変を認め、褐色細胞腫と診断した。α-blocker内服後、腹腔鏡下右副腎腫瘍摘出術を施行した。VHL解析で、患児および父に既報のR161Q変異をヘテロ接合性に同定した。患児、父ともに褐色細胞腫以外の病変はなく、VHL病type 2Cと考えた。小児期発症の褐色細胞腫では、VHL病を含めた遺伝子異常の関与を考慮すべきである。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00643&link_issn=&doc_id=20150126200019&doc_link_id=%2Fag1snrsd%2F2015%2F006801%2F020%2F0125-0130%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag1snrsd%2F2015%2F006801%2F020%2F0125-0130%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • 低身長を契機に診断された新規変異(L677Q)を認めるIGSF1異常症の一男児例

    佐藤 温洋, 冨田 雄一郎, 深見 真紀, 入月 浩美, 長崎 啓祐

    日本内分泌学会雑誌   90 ( 2 )   527 - 527   2014年9月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • 偽性副甲状腺機能低下症に対する分子遺伝学的解析のアルゴリズムの作成

    長崎 啓祐, 入月 浩美, 佐藤 英利, 佐野 伸一朗, 深見 真紀, 齋藤 昭彦

    新潟県医師会報   ( 765 )   7 - 9   2013年12月

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    記述言語:日本語   出版者・発行元:新潟県医師会  

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  • SLC26A4とDUOX2のヘテロ接合性変異を認めた甲状腺ホルモン合成障害による先天性甲状腺機能低下症の1例

    長崎 啓祐, 佐藤 英利, 入月 浩美, 小川 洋平, 菊池 透, 浅見 直, 深見 真紀

    日本内分泌学会雑誌   89 ( 2 )   463 - 463   2013年9月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • Autonomously functioning thyroid nodule in a four-year-old boy with Sotos syndrome. 国際誌

    Hiromi Nyuzuki, Keisuke Nagasaki, Hiroshi Matsuyama, Masahiko Tomita, Chihaya Imai, Yohei Ogawa, Toru Kikuchi, Makoto Uchiyama

    Pediatrics international : official journal of the Japan Pediatric Society   53 ( 1 )   137 - 8   2011年2月

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MISC

  • 学校糖尿病検診における要精査者抽出の効率性や精度に関する検討

    小川 洋平, 長崎 啓祐, 入月 浩美, 澤野 堅太郎, 柴田 奈央, 廣嶋 省太, 齋藤 昭彦

    糖尿病   65 ( Suppl.1 )   S - 273   2022年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • 新潟県における小児1型糖尿病発症率の年次推移の検討

    澤野 堅太郎, 小川 洋平, 長崎 啓祐, 廣嶋 省太, 柴田 奈央, 入月 浩美, 齋藤 昭彦

    糖尿病   65 ( Suppl.1 )   S - 205   2022年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • 小児1型糖尿病におけるミニメド640Gからメディセーフウィズへ機種変更した際の使用感や満足度の変化

    小川 洋平, 長崎 啓祐, 入月 浩美, 澤野 堅太郎, 小貫 孝則, 廣嶋 省太, 齋藤 昭彦

    糖尿病   64 ( Suppl.1 )   I - 4   2021年5月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • 新潟県における小児期発症1型糖尿病の小児科から成人科への診療移行に関する実態調査

    小川 洋平, 長崎 啓祐, 入月 浩美, 澤野 堅太郎, 菊池 透, 齋藤 昭彦

    糖尿病   63 ( Suppl.1 )   S - 178   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • GALMの両アレル性変異はガラクトース血症IV型を呈する 査読

    和田 陽一, 菊池 敦生, 市野井 那津子, 坂本 修, 岩澤 伸哉, 竹澤 祐介, 新堀 哲也, 入月 浩美, 中島 葉子, 小川 えりか, 石毛 美夏, 平井 洋生, 笹井 英雄, 藤木 亮次, 伊藤 哲哉, 小原 收, 青木 洋子, 深尾 敏幸, 呉 繁夫

    日本先天代謝異常学会雑誌   35   114 - 114   2019年9月

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    記述言語:日本語   出版者・発行元:日本先天代謝異常学会  

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  • ビタミンD欠乏を合併した副甲状腺機能低下症の13歳男児

    田屋 光将, 入月 浩美, 佐々木 直, 小川 洋平, 長崎 啓祐, 齋藤 昭彦

    日本小児科学会雑誌   123 ( 6 )   1061 - 1061   2019年6月

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    記述言語:日本語   出版者・発行元:(公社)日本小児科学会  

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  • 小児期発症1型糖尿病患者における診断時年齢・罹病期間と成人期血糖コントロールとの関連

    小川 洋平, 長崎 啓祐, 佐々木 直, 入月 浩美, 齋藤 昭彦

    糖尿病   62 ( Suppl.1 )   S - 282   2019年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • GALMの両アレル性変異はガラクトース血症IV型を呈する(Blallelic GALM pathogenic variants cause a novel type of galactosemia)

    和田 陽一, 菊池 敦生, 市野井 那津子, 坂本 修, 竹澤 祐介, 岩澤 伸哉, 新堀 哲也, 入月 浩美, 中島 葉子, 小川 えりか, 石毛 美夏, 平井 洋生, 笹井 英雄, 藤木 亮次, 伊藤 哲也, 小原 収, 青木 洋子, 小柴 生造, 深尾 敏幸, 呉 繁夫

    日本小児科学会雑誌   123 ( 2 )   280 - 280   2019年2月

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    記述言語:英語   出版者・発行元:(公社)日本小児科学会  

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  • GALMの両アレル性変異はガラクトース血症IV型を呈する(Blallelic GALM pathogenic variants cause a novel type of galactosemia)

    和田 陽一, 菊池 敦生, 市野井 那津子, 坂本 修, 竹澤 祐介, 岩澤 伸哉, 新堀 哲也, 入月 浩美, 中島 葉子, 小川 えりか, 石毛 美夏, 平井 洋生, 笹井 英雄, 藤木 亮次, 伊藤 哲也, 小原 収, 青木 洋子, 小柴 生造, 深尾 敏幸, 呉 繁夫

    日本小児科学会雑誌   123 ( 2 )   280 - 280   2019年2月

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    記述言語:英語   出版者・発行元:(公社)日本小児科学会  

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  • 新潟県におけるタンデムマス法を用いた新生児スクリーニング導入後の現況

    入月 浩美, 佐藤 英利, 小川 洋平, 長崎 啓祐, 菊池 透, 齋藤 昭彦, 浅見 直

    日本小児科学会雑誌   118 ( 7 )   1140 - 1140   2014年7月

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    記述言語:日本語   出版者・発行元:(公社)日本小児科学会  

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共同研究・競争的資金等の研究

  • PNPLA4機能不全がもたらすミトコンドリア異常症及び乳児突然死の発症機序解明

    研究課題/領域番号:21K15860

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業 若手研究

    研究種目:若手研究

    提供機関:日本学術振興会

    入月 浩美

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    本研究の目的は、PNPLA4の分子生物学的機能を明らかとし、小児希少難病であるミトコンドリア呼吸鎖異常症の病態を解明することである。PNPLA4は申請者らがミトコンドリア呼吸鎖異常症の新規原因遺伝子として同定した遺伝子であり、本研究でその機能を解明する意義は大きい。PNPLA4の生体内での役割を解明するためにはモデル生物を用いた研究が必要不可欠だが、本遺伝子はマウスでは発現していない。そのため、申請者らはモデル生物としてpnpla4ノックアウトゼブラフィッシュを世界に先駆けて作製し、既に機能解析を進めている。ゼブラフィッシュは世代時間が短く、遺伝学やイメージング解析で非常に優れている。全ゲノム配列はヒトと高い相同性を有し、遺伝子数や主要臓器・組織の発生および構造もヒトとの類似性が高い。本研究を通してPNPLA4の詳細な分子生物学的機能が明らかとなれば、ミトコンドリア呼吸鎖異常症の新たな治療戦略の創出ならびに乳児突然死の発症予防に大きく寄与する可能性がある。本研究では既に、ホールマウントのin situハイブリダイゼーション法の結果から、ゼブラフィッシュ脳及び筋組織においてpnpla4 mRNAの発現が高いことを発見した。また、pnpla4ノックアウトゼブラフィッシュ脳を用いた網羅的脂質解析を実施し、トリアシルグリセロールの代謝異常を示唆する結果を得ている。現在、ゼブラフィッシュの筋組織、及び、PNPLA4ノックダウン細胞を試料とした網羅的脂質解析を実施し、既存の実験結果と照合してPNPLA4標的脂質の絞り込みを行っているところである。

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  • 本邦における中枢性甲状腺機能低下症の診療状況および分子遺伝学的検討

    研究課題/領域番号:18K10024

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    長崎 啓祐, 沼倉 周彦, 入月 浩美

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    本研究の目的は、本邦における中枢性甲状腺機能低下症(以下中枢性CH)の臨床像および分子基盤を明らかにすることである。本研究の結果を踏まえ、今後本邦においてFT4スクリーニングを導入すべきか否か議論していく予定である。
    研究成果:2019年度は、引き続きTSH単独欠損症の分子遺伝学的解析につき検討をすすめた。TSH単独欠損症の遺伝学的解析(G2018-0007)として倫理承認を取得後に、対象症例の所属する施設より検体を収集した。対象症例は23例であった。このうち、母体バセドウ病による一過性甲状腺機能低下症2例、TBG欠損症1例、一過性の甲状腺機能低下症5例、同意取得が得られない症例1例を除外した。残り14例のうち、すでに他施設で遺伝子解析を行ってていた症例が6例いたことが判明し、残り8例の遺伝子解析をすすめた。今年度に7例の遺伝子解析を修了し、残り1例の解析を行っている。その他、依頼のあった数件の中枢性CH症例の遺伝子解析を行っている。
    他施設での解析結果と合わせて、今年度成果を論文化する予定である。本邦において、中枢性CHの約半数はIGSF-1遺伝子異常であること、そのほとんどはFT4スクリーニングを行っている地域から出生した児であることが明らかになっている。FT4スクリーニングを実施してない地域では、中枢性CHが見逃されている可能性が示唆された。中枢性CHの臨床像の調査については、本邦で行われた二次調査のまとめからすでに治療状況や発達状況を確認している。
    また共同研究者の在籍する山形県ではFT4スクリーニングを実施しており、平成30年度は7786件の検査を行ったが明らかな中枢性CHの患者は存在しなかった。令和元年度も現在まで、先天性中枢性CHの検出はない。今後、FT4スクリーニングによる中枢性CHの発見頻度など明らかにする予定である。

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  • 乳児突然死に関連したミトコンドリア呼吸鎖異常症の原因遺伝子PNPAL4の機能解明

    研究課題/領域番号:18K15662

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業 若手研究

    研究種目:若手研究

    提供機関:日本学術振興会

    入月 浩美

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    本研究の目的は、PNPLA4の分子生物学的機能を明らかとし、小児の希少難病であるミトコンドリア呼吸鎖異常症および乳児突然死症候群/乳児突発性危急事態の 新たな発症機序を解明することである。本遺伝子は、乳児突発性危急事態として発症したミトコンドリア呼吸鎖異常症患者において、我々が同定した原因遺伝子 であり、マウスを除く多様な生物種に発現してリン脂質代謝に関与するが、その詳細は未だ不明である。PNPLA4の生体内での役割を解明するためにはモデル生物 を用いた研究が必要不可欠だが、本遺伝子はマウスでは発現していない。そのため、我々はモデル生物としてゼブラフィッシュを選択した。ゼブラフィッシュは 世代時間が短く、遺伝学やイメージング解析で非常に優れている。また、CRISPR/Cas9システムなどによって容易に疾患モデルを作製することが可能な脊椎動物 である。全ゲノム配列はヒトと高い相同性を有し、遺伝子数や主要臓器・組織の発生および構造もヒトとの類似性が高い。本研究を通してPNPLA4の詳細な分子メ カニズムが明らかとなれば、ミトコンドリア呼吸鎖異常症の新たな治療戦略の創出ならびに乳児突然死の予防法提唱に大きく寄与する可能性がある。
    本研究では、現在までに、CRISPR/Cas9システムを用いて疾患モデルとなるpnpla4ノックアウトゼブラフィッシュの樹立に成功した。現在、pnpla4ノックアウトゼブラフィッシュを用いて、タンパク発現解析、網羅的脂質解析、組織学的解析等の手法によって表現型を評価しているところである。今後、ミトコンドリア呼吸鎖複合体活性と脂質代謝への影響をさらに詳細に調べることで、変異pnpla4が及ぼす生体への影響と脂質代謝への関与を明らかとする予定である。

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