Details of a Researcher - Narumi, Satoshi

Papers - Narumi, Satoshi

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サイログロブリン遺伝子異常による先天性甲状腺機能低下症4例の臨床的比較検討

川北葵, 山本幸代, 久保和泰, 江口真美, 齋藤玲子, 後藤元秀, 川越倫子, 河田泰定, 鳴海覚志, 長谷川奉延, 楠原浩一

日本内分泌学会雑誌 ((一社)日本内分泌学会) 93 ( 1 ) 261 - 261 2017.04

ISSN 0029-0661

A novel heterozygous intronic mutation in POU1F1 is associated with combined pituitary hormone deficiency

Masaki Takagi, Hotaka Kamasaki, Hiroko Yagi, Ryuji Fukuzawa, Satoshi Narumi, Tomonobu Hasegawa

ENDOCRINE JOURNAL (JAPAN ENDOCRINE SOC) 64 ( 2 ) 229 - 234 2017.02

Accepted, ISSN 0918-8959

POU class 1 homeobox 1 (POUlFi) regulates pituitary cell- specific gene expression of somatotropes, lactotropes, and thyrotropes. In humans, two POUlF1 isoforms (long and short isoform), which are generated by the alternative use of the splice acceptor site for exon 2, have been identified. To date, more than 30 POU1F1 mutations in patients with combined pituitary hormone deficiency (CPHD) have been described. All POU1F1 variants reported to date affect both the short and long isoforms of the POUlF I protein; therefore, it is unclear at present whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans. Here, we described a sibling case of CPHD carrying a heterozygous mutation in intron 1 of POU1F1. In vitro experiments showed that this mutation resulted in exon 2- skipping of only in the short isoform of POU1F1, while the long isoform remained intact. This result strongly suggests the possibility, for the first time, that isolated mutations in the short isoform of POU1Fi could be sufficient for induction of POU1Fl- related CPHD. This finding improves our understanding of the molecular mechanisms, and developmental course associated with mutations in POU1F1.

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TSH受容体細胞内ドメインの系統的変異導入研究どのようなナンセンス/フレームシフトバリアントが機能低下をきたすか?

杉澤千穂, 阿部清美, 谷山松雄, 長谷川奉延, 鳴海覚志

日本内分泌学会雑誌 ((一社)日本内分泌学会) 92 ( 3 ) 607 - 607 2017.01

ISSN 0029-0661

A de novo 50-bp GNAS Intragenic Duplication in a Patient with Pseudohypoparathyroidism Type 1a.

Erina Suzuki, Ryosuke Bo, Kaori Sue, Hiroyuki Awano, Tsutomu Ogata, Satoshi Narumi, Masayo Kagami, Shinichiro Sano, Maki Fukami

Cytogenetic and genome research 153 ( 3 ) 125 - 130 2017

Accepted, ISSN 1424-8581

Germline intragenic mutations in the GNAS locus result in pseudohypoparathyroidism type 1a (PHP1a) and related conditions. Nearly half of the previously reported GNAS intragenic mutations were structural variants, including 3 tandem duplications of 12-25 bp. However, the precise mutation spectrum and the genomic basis of GNAS structural variants remain to be clarified. Here, we report a de novo 50-bp tandem duplication in GNAS (c.723_772dup50, p.Glu259Leufs*29) identified in a patient with typical clinical features of PHP1a. The mutant transcript was predicted to undergo mRNA decay or encode a nonfunctional protein. The 2 breakpoints of the duplication shared a 1-bp microhomology but were not associated with long homology or nucleotide stretches. We also examined the breakpoint structures of 3 previously reported GNAS duplications and found that 1 had a structure similar to that of our case, while the remaining 2 had blunt-ended breakpoints without microhomologies. In silico analyses revealed that the GNAS-flanking region was not enriched with repeats, palindromes, noncanonical DNA motifs, or GC content. This study expands the mutation spectrum of GNAS and provides the first indication that GNAS intragenic structural variants are induced by multiple processes, including nonhomologous end-joining and/or microhomology-mediated break-induced replication, independently of known rearrangement-inducing DNA features.

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A MIRAGE SYNDROME PATIENT WITHOUT HEMATOLOGICAL PHENOTYPES: INACTIVATION OF A GERMLINE ACTIVATING SAMD9 MUTATION BY A SOMATICALLY ACQUIRED NONSENSE MUTATION IN HEMATOPOIETIC CELLS

Shima Hirohito, Nomura Yumiko, Sugimoto Kazuhiko, Satoh Akira, Ogata Tsutomu, Fukami Maki, Narumi Satoshi

HORMONE RESEARCH IN PAEDIATRICS 88 49 - 50 2017

Accepted, ISSN 1663-2818

PROTEIN-TRUNCATING MUTATION IN "GENE A" IN A GIRL WITH CENTRAL PRECOCIOUS PUBERTY: IMPLICATIONS FOR A NOVEL GAIN-OF-FUNCTION MECHANISM OF G-PROTEIN COUPLED RECEPTORS

Fukami Maki, Suzuki Erina, Izumi Yoko, Torii Tomohiro, Igarashi Maki, Miyado Mami, Narumi Satoshi, Katsumi Momori, Yamauchi Junji, Fujisawa Yasuko, Ogata Tsutomu

HORMONE RESEARCH IN PAEDIATRICS 88 547 2017

Accepted, ISSN 1663-2818

Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome

Koki Nagai, Hirohito Shima, Miki Kamimura, Junko Kanno, Erina Suzuki, Akira Ishiguro, Satoshi Narumi, Shigeo Kure, Ikuma Fujiwara, Maki Fukami

Cytogenetic and Genome Research (S. Karger AG) 151 ( 1 ) 1 - 4 2017

Accepted, ISSN 1424-8581

The Xp22.31 region is characterized by a low frequency of interspersed repeats and a low GC content. Submicroscopic deletions at Xp22.31 involving STS and ANOS1 (alias KAL1) underlie X-linked ichthyosis and Kallmann syndrome, respectively. Of the known microdeletions at Xp22.31, a common approximately 1.5-Mb deletion encompassing STS was ascribed to nonallelic homologous recombination, while 2 ANOS1-containing deletions were attributed to nonhomologous end-joining. However, the genomic bases of other microdeletions within the Xp22.31 region remain to be elucidated. Here, we identified a 2,735,696-bp deletion encompassing STS and ANOS1 in a boy with X-linked ichthyosis and Kallmann syndrome. The breakpoints of the deletion were located within Alu repeats and shared 2-bp microhomology. The fusion junction was not associated with nucleotide stretches, and the breakpoint-flanking regions harbored no palindromes or noncanonical DNA motifs. These results indicate that microhomology-mediated break-induced replication (MMBIR) can cause deletions at Xp22.31, resulting in contiguous gene deletion syndrome. It appears that interspersed repeats without other known rearrangement-inducing DNA features or high GC contents are sufficient to stimulate MMBIR at Xp22.31.

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Three-Quarters Adrenalectomy for Infantile-Onset Cushing Syndrome due to Bilateral Adrenal Hyperplasia in McCune-Albright Syndrome

Tomoyo Itonaga, Hironori Goto, Manabu Toujigamori, Yasuharu Ohno, Seigo Korematsu, Tatsuro Izumi, Satoshi Narumi, Tomonobu Hasegawa, Kenji Ihara

Hormone Research in Paediatrics (S. Karger AG) 88 ( 3-4 ) 285 - 290 2017

Accepted, ISSN 1663-2818

Background: Bilateral adrenalectomy is performed in cases with infantile-onset Cushing syndrome due to bilateral adrenal hyperplasia in McCune-Albright syndrome (MAS) because severe Cushing syndrome with heart failure and liver dysfunction can have a lethal outcome. This procedure can completely ameliorate hypercortisolism, although lifetime steroid replacement therapy and steps to prevent adrenal crisis are necessary. Recently, the efficacy of unilateral adrenalectomy has been reported in adult cases of bilateral macronodular adrenal hyperplasia, but there is no consensus regarding the appropriate surgical treatment for bilateral adrenal hyperplasia in MAS. Objective: A 6-month-old girl presented with café-au-lait spots, short stature, central obesity, a moon face, and hypertension. Endocrinological tests and imaging studies led to the diagnosis of ACTH-independent Cushing syndrome due to bilateral adrenal hyperplasia induced by MAS. "Three-quarters adrenalectomy", namely right-sided total adrenalectomy and left-sided half adrenalectomy, was carried out. An activating mutation of the GNAS1 gene (p.Arg201Cys) was identified in the adrenal tissues. Since the operation, our patient has been in a state of clinical remission for more than 2 years. Conclusion: Our original surgical intervention, three-quarters adrenalectomy, may be a new treatment option for Cushing syndrome associated with MAS.

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Syndromic disorder of sex development due to a novel hemizygous mutation in the carboxyl-terminal domain of ATRX.

Masaki Takagi, Hiroko Yagi, Ryuji Fukuzawa, Satoshi Narumi, Tomonobu Hasegawa

Human genome variation 4 17012 - 17012 2017

ISSN 2054-345X

Alpha-thalassemia/mental retardation syndrome X-linked (ATRX; OMIM #301040), which is caused by mutations in the ATRX gene, is characterized by alpha-thalassemia, distinct dysmorphic facies, psychomotor development delay and genital abnormalities. Here, we describe a neonatal case of syndromic disorder of sex development, harboring a novel hemizygous mutation, p.Asp2352fs*1 in the carboxyl-terminal domain of ATRX. Our study provides additional evidence that deletion of the carboxyl terminus of ATRX is associated with severe genital anomalies.

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A novel dominant negative mutation in the intracellular domain of GHR is associated with growth hormone insensitivity.

Takagi M, Shinohara H, Nagashima Y, Hasegawa Y, Narumi S, Hasegawa T

Clinical endocrinology 85 ( 4 ) 669 - 71 2016.10

ISSN 0300-0664

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A patient with pseudohypoaldosteronism type II complicated by congenital hypopituitarism carrying a KLHL3 mutation

Marie Mitani, Munehiro Furuichi, Satoshi Narumi, Tomonobu Hasegawa, Motoko Chiga, Shinichi Uchida, Seiji Sato

Clinical Pediatric Endocrinology (Jeff Corporation Co. Ltd) 25 ( 4 ) 127 - 134 2016.10

Accepted, ISSN 0918-5739

Pseudohypoaldosteronism type II (PHA II) is a renal tubular disease that causes hyperkalemia, hypertension, and metabolic acidosis. Mutations in four genes (WNK4, WNK1, KLHL3, and CUL3) are known to cause PHA II. We report a patient with PHA II carrying a KLHL3 mutation, who also had congenital hypopituitarism. The patient, a 3-yr-old boy, experienced loss of consciousness at age 10 mo. He exhibited growth failure, hypertension, hyperkalemia, and metabolic acidosis. We diagnosed him as having PHA II because he had low plasma renin activity with normal plasma aldosterone level and a low transtubular potassium gradient. Further investigations revealed defective secretion of GH and gonadotropins and anterior pituitary gland hypoplasia. Genetic analyses revealed a previously known heterozygous KLHL3 mutation (p.Leu387Pro), but no mutation was detected in 27 genes associated with congenital hypopituitarism. He was treated with sodium restriction and recombinant human GH, which normalized growth velocity. This is the first report of a molecularly confirmed patient with PHA II complicated by congenital hypopituitarism. We speculate that both GH deficiency and metabolic acidosis contributed to growth failure. Endocrinological investigations will help to individualize the treatment of patients with PHA II presenting with growth failure.

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SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7

Satoshi Narumi, Naoko Amano, Tomohiro Ishii, Noriyuki Katsumata, Koji Muroya, Masanori Adachi, Katsuaki Toyoshima, Yukichi Tanaka, Ryuji Fukuzawa, Kenichi Miyako, Saori Kinjo, Shouichi Ohga, Kenji Ihara, Hirosuke Inoue, Tadamune Kinjo, Toshiro Hara, Miyuki Kohno, Shiro Yamada, Hironaka Urano, Yosuke Kitagawa, Koji Tsugawa, Asumi Higa, Masakazu Miyawaki, Takahiro Okutani, Zenro Kizaki, Hiroyuki Hamada, Minako Kihara, Kentaro Shiga, Tetsuya Yamaguchi, Manabu Kenmochi, Hiroyuki Kitajima, Maki Fukami, Atsushi Shimizu, Jun Kudoh, Shinsuke Shibata, Hideyuki Okano, Noriko Miyake, Naomichi Matsumoto, Tomonobu Hasegawa

Nature Genetics (Nature Publishing Group) 48 ( 7 ) 792 - 797 2016.07

ISSN 1546-1718

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

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SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7

NATURE GENETICS (NATURE PUBLISHING GROUP) 48 ( 7 ) 792 - + 2016.07

Accepted, ISSN 1061-4036

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新生児マス・スクリーニングで発見され、DUOX2遺伝子変異が確認された一過性甲状腺機能低下症の1例

石田倫也, 松浦信夫, 白井宏幸, 石井正浩, 鳴海覚志, 阿部清美

神奈川医学会雑誌 ((公社)神奈川県医師会) 43 ( 2 ) 315 - 315 2016.07

ISSN 0285-0680

SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.

Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, Toyoshima K, Tanaka Y, Fukuzawa R, Miyako K, Kinjo S, Ohga S, Ihara K, Inoue H, Kinjo T, Hara T, Kohno M, Yamada S, Urano H, Kitagawa Y, Tsugawa K, Higa A, Miyawaki M, Okutani T, Kizaki Z, Hamada H, Kihara M, Shiga K, Yamaguchi T, Kenmochi M, Kitajima H, Fukami M, Shimizu A, Kudoh J, Shibata S, Okano H, Miyake N, Matsumoto N, Hasegawa T

Nature genetics 48 ( 7 ) 792 - 7 2016.07

ISSN 1061-4036

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A novel mutation in HESX1 causes combined pituitary hormone deficiency without septo optic dysplasia phenotypes

Masaki Takagi, Mai Takahashi, Yoshiaki Ohtsu, Takeshi Sato, Satoshi Narumi, Hirokazu Arakawa, Tomonobu Hasegawa

Endocrine Journal (Japan Endocrine Society) 63 ( 4 ) 405 - 10 2016.04

Accepted, ISSN 0918-8959

Heterozygous and/or homozygous HESX1 mutations have been reported to cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD), in association with septo optic dysplasia (SOD). We report a novel heterozygous HESX1 mutation in a CPHD patient without SOD phenotypes. The propositus was a oneyear- old Japanese girl. Shortly after birth, she was found to be hypoglycemic. She was diagnosed with central adrenal insufficiency based on low cortisol and ACTH at a time of severe hypoglycemia. Further endocrine studies indicated that the patient also had central hypothyroidism and growth hormone deficiency. Using a next-generation sequencing strategy, we identified a novel heterozygous HESX1 mutation, c.326G&gt
A (p.Arg109Gln). Western blotting and subcellular localization revealed no significant difference between wild type and mutant HESX1. Electrophoretic mobility shift assays showed that the mutant HESX1 abrogated DNA-binding ability. Mutant HESX1 was unable to repress PROP1-mediated activation. In conclusion, this study identified Arg109 as a critical residue in the HESX1 protein and extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in HESX1. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.

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複合型下垂体前葉機能低下症と診断されていたIGSF1異常症の1例

朝倉由美, 阿部清美, 花川純子, 島田綾, 室谷浩二, 鳴海覚志, 長谷川奉延, 安達昌功

日本内分泌学会雑誌 ((一社)日本内分泌学会) 92 ( 1 ) 221 - 221 2016.04

ISSN 0029-0661

Stippled calcification in an infant with a recurrent SRCAP gene mutation.

Yagi H, Takagi M, Narumi S, Hasegawa T, Nishimura G, Hasegawa Y

American journal of medical genetics. Part A 170A ( 4 ) 1088 - 91 2016.04

ISSN 1552-4825

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ヒストンメチル基転移酵素SETD2遺伝子変異を認めた巨人症の一例

隅田健太郎, 鳴海覚志, 福岡秀規, 井口元三, 小武由紀子, 吉田健一, 松本隆作, 坂東弘教, 西沢衡, 高橋路子, 小川渉, 長谷川奉延, 高橋裕

日本内分泌学会雑誌 ((一社)日本内分泌学会) 92 ( 1 ) 301 - 301 2016.04

ISSN 0029-0661

Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2

Atsuko Yoshizawa-Ogasawara, Kiyomi Abe, Sayaka Ogikubo, Satoshi Narumi, Tomonobu Hasegawa, Mari Satoh

JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM (WALTER DE GRUYTER GMBH) 29 ( 3 ) 363 - 371 2016.03

Accepted, ISSN 0334-018X

Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (DUOX2) occurring along with concurrent missense mutations in thyroid peroxidase (TPO), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in DUOX2; one of them was also heterozygous for p.[R361L] in TPO. The third patient was compound heterozygous for p.[L1160del]+[R1334W] in DUOX2 and heterozygous for p.[P883S] in TPO. This is the first report of a de novo L1160del mutation affecting the DUOX2 gene and of the novel mutations Y1180X in DUOX2 and R361L in TPO. R1110Q and L1160del were found to reduce H2O2 production (5%-9%, p < 0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H2O2 production (-0.7%+/- 0.6%, p < 0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H2O2 production (24%+/- 0.9%, p < 0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in TPO, caused partial reduction in peroxidase activity (20.6%+/- 0.8%, p = 0.01), whereas P883S, a missense variant, increased it (133.7%+/- 2.8%, p = 0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway.

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