論文 - 鳴海　覚志

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年

査読有り,  ISSN  1663-2818

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年

査読有り,  ISSN  1663-2818

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

Takagi M, Yagi H, Fukuzawa R, Narumi S, Hasegawa T

Human genome variation 4   17012 - 17012 2017年

ISSN  2054-345X

　概要を見る

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

Nagai K, Shima H, Kamimura M, Kanno J, Suzuki E, Ishiguro A, Narumi S, Kure S, Fujiwara I, Fukami M

Cytogenetic and genome research （S. Karger AG）  151 （ 1 ） 1 - 4 2017年

査読有り,  ISSN  1424-8581

　概要を見る

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.

Itonaga T, Goto H, Toujigamori M, Ohno Y, Korematsu S, Izumi T, Narumi S, Hasegawa T, Ihara K

Hormone research in paediatrics （S. Karger AG）  88 （ 3-4 ） 285 - 290 2017年

査読有り,  ISSN  1663-2818

　概要を見る

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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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年10月

ISSN  0300-0664

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

Mitani M, Furuichi M, Narumi S, Hasegawa T, Chiga M, Uchida S, Sato S

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology （Jeff Corporation Co. Ltd）  25 （ 4 ） 127 - 134 2016年10月

査読有り,  ISSN  0918-5739

　概要を見る

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年07月

ISSN  1546-1718

　概要を見る

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

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 - + 2016年07月

査読有り,  ISSN  1061-4036

　概要を見る

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.

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年07月

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年07月

ISSN  0285-0680

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

Takagi M, Takahashi M, Ohtsu Y, Sato T, Narumi S, Arakawa H, Hasegawa T

Endocrine journal （Japan Endocrine Society）  63 （ 4 ） 405 - 10 2016年04月

査読有り,  ISSN  0918-8959

　概要を見る

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年04月

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年04月

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年04月

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年03月

査読有り,  ISSN  0334-018X

　概要を見る

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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Whole exome sequencing identified a novel COL2A1 mutation that causes mild Spondylo-epiphyseal dysplasia mimicking autosomal dominant brachyolmia.

Takagi M, Shimizu M, Suzuki E, Shinohara H, Narumi S, Hasegawa T, Nishimura G, Hasegawa Y

American journal of medical genetics. Part A （WILEY-BLACKWELL）  170 （ 3 ） 795 - 8 2016年03月

査読有り,  ISSN  1552-4825

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A novel mutation of the THRB gene in a Japanese family with resistance to thyroid hormone.

Ito J, Narumi S, Nishizawa K, Kamimaki T, Hori N, Hasegawa T

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 25 （ 1 ） 19 - 22 2016年01月

査読有り,  ISSN  0918-5739

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Complex X-Chromosomal Rearrangements in Two Women with Ovarian Dysfunction: Implications of Chromothripsis/Chromoanasynthesis-Dependent and -Independent Origins of Complex Genomic Alterations.

Suzuki E, Shima H, Toki M, Hanew K, Matsubara K, Kurahashi H, Narumi S, Ogata T, Kamimaki T, Fukami M

Cytogenetic and genome research （KARGER）  150 （ 2 ） 86 - 92 2016年

査読有り,  ISSN  1424-8581

　概要を見る

Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndromeassociated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by arraybased comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing. Patient 1 carried a rearrangement of unknown parental origin with a 46, X, der(X)(pter -> p22.1:: p11.23 -> q24:: q21.3 -> q24:: p11.4 -> pter) karyotype, indicative of a catastrophic chromosomal reconstruction due to chromothripsis/chromoanasynthesis. Patient 2 had a paternally derived isochromosome with a 46, X, der(X)(pter. p22.31:: q22.1 -> q10:: q10 -> q22.1:: p22.31 -> pter) karyotype, which likely resulted from 2 independent, sequential events. Both patients showed completely skewed X inactivation. CpG sites at Xp22.3 were hypermethylated in patient 2. The results indicate that germline complex X-chromosomal rearrangements underlie nonsyndromic ovarian dysfunction and Turner syndrome. Disease-causative mechanisms of these rearrangements likely include aberrant DNA methylation, in addition to X-chromosomal mispairing and haplo-insufficiency of genes escaping X inactivation. Notably, our data imply that germline complex X-chromosomal rearrangements are created through both chromothripsis/chromoanasynthesis-dependent and - independent processes. (C) 2017 S. Karger AG, Basel

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NR0B1 Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty.

Shima H, Yatsuga S, Nakamura A, Sano S, Sasaki T, Katsumata N, Suzuki E, Hata K, Nakabayashi K, Momozawa Y, Kubo M, Okamura K, Kure S, Matsubara Y, Ogata T, Narumi S, Fukami M

Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 10 （ 4 ） 205 - 209 2016年

査読有り,  ISSN  1661-5425

　概要を見る

NR0B1 is the causative gene for X-linked adrenal hypoplasia congenita, characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and infertility. We identified an NR0B1 frameshift mutation in a boy with precocious puberty who had no signs of adrenal insufficiency. Blood examination revealed elevated testosterone levels and gonadotropin hyperresponses to gonadotropin releasing hormone (GnRH) stimulation, together with normal adrenal hormone levels. GnRH analog treatment partially ameliorated his clinical features. Molecular analysis identified a p.Glu3fsAla*16 in NR0B1. These results expand the clinical manifestations of NR0B1 mutations to include central precocious puberty without adrenal insufficiency. NR0B1 mutations likely underlie androgen overproduction via GnRH-dependent and -independent mechanisms.

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