Papers - Narumi, Satoshi

Whole Exome Sequencing Identified a Novel COL2A1 Mutation That Causes Mild Spondylo-Epiphyseal Dysplasia Mimicking Autosomal Dominant Brachyolmia

Masaki Takagi, Mika Shimizu, Eri Suzuki, Hiroyuki Shinohara, Satoshi Narumi, Tomonobu Hasegawa, Gen Nishimura, Yukihiro Hasegawa

AMERICAN JOURNAL OF MEDICAL GENETICS PART A (WILEY-BLACKWELL)  170 ( 3 ) 795 - 8 2016.03

Accepted,  ISSN  1552-4825

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

Jumpei Ito, Satoshi Narumi, Kazumichi Nishizawa, Tsutomu Kamimaki, Naoaki Hori, Tomonobu Hasegawa

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 25 ( 1 ) 19 - 22 2016.01

Accepted,  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

Erina Suzuki, Hirohito Shima, Machiko Toki, Kunihiko Hanew, Keiko Matsubara, Hiroki Kurahashi, Satoshi Narumi, Tsutomu Ogata, Tsutomu Kamimaki, Maki Fukami

CYTOGENETIC AND GENOME RESEARCH (KARGER)  150 ( 2 ) 86 - 92 2016

Accepted,  ISSN  1424-8581

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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.

Hirohito Shima, Shuichi Yatsuga, Akie Nakamura, Shinichiro Sano, Takako Sasaki, Noriyuki Katsumata, Erina Suzuki, Kenichiro Hata, Kazuhiko Nakabayashi, Yukihide Momozawa, Michiaki Kubo, Kohji Okamura, Shigeo Kure, Yoichi Matsubara, Tsutomu Ogata, Satoshi Narumi, Maki Fukami

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

Accepted,  ISSN  1661-5425

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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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Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice.

Kotajima-Murakami H, Narumi S, Yuzaki M, Yanagihara D

PloS one 11 ( 11 ) e0166144 2016

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偽性副甲状腺機能低下症の視床下部 下垂体甲状腺軸の特徴

阿部 清美, 鳴海 覚志, 三井 俊賢, 長崎 啓祐, 中村 明枝, 田島 敏広, 湯野 暁子, 臼井 健, 室谷 浩二, 朝倉 由美, 安達 昌功, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  91 ( 2Suppl. ) 74 - 74 2015.11

ISSN  0029-0661

本邦初のDUOXA2変異による先天性甲状腺機能低下症の1例

杉澤 千穂, 樋口 真司, 高木 優樹, 長谷川 行洋, 長崎 啓祐, 谷山 松雄, 阿部 清美, 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)  91 ( 2Suppl. ) 75 - 75 2015.11

ISSN  0029-0661

MIRAGE症候群 副腎皮質機能低下症を含む多彩な症状で新生児期に発症する新規疾患概念確立と責任遺伝子同定

長谷川 奉延, 木原 美奈子, 北川 陽介, 津川 浩二, 河野 美幸, 浦野 博央, 豊島 勝昭, 釼持 学, 北島 博之, 比嘉 明日美, 宮脇 正和, 奥谷 貴弘, 井上 普介, 金城 唯宗, 井原 健二, 天野 直子, 鳴海 覚志, 石井 智弘

日本新生児成育医学会雑誌 ((公社)日本新生児成育医学会)  27 ( 3 ) 531 - 531 2015.09

ISSN  2189-7549

Pseudodominant inheritance in a family with nonautoimmune hypothyroidism due to biallelic DUOX2 mutations

Kiyomi Abe, Satoshi Narumi, Ayuko S. Suwanai, Takashi Hamajima, Tomonobu Hasegawa

CLINICAL ENDOCRINOLOGY (WILEY-BLACKWELL)  83 ( 3 ) 394 - 8 2015.09

Accepted,  ISSN  0300-0664

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ObjectivesMutations in the dual oxidase 2 gene (DUOX2) is the most common genetic cause of congenital hypothyroidism (CH) in Japan. All previously described DUOX2 mutation-carrying families have followed autosomal recessive inheritance. We report a nonconsanguineous Japanese family harbouring biallelic DUOX2 mutations, which presented an apparently dominant inheritance of nonautoimmune hypothyroidism.
Design and methodsThe proband and her two sisters had been diagnosed as having CH on newborn screening and were treated with levothyroxine. Their mother had subclinical hypothyroidism. We sequenced DUOX2 in the proband and her family members. Pathogenicity of the identified novel mutation (p.Y1347C) was verified in vitro.
ResultsWe found that the proband and her sisters were compound heterozygous for a novel DUOX2 mutation p.Y1347C and a previously reported functional variant p.H678R. Unexpectedly, we found that the mother was homozygous for p.H678R. Expression experiments showed that the p.Y1347C mutant had reduced H2O2-producing activity, although there was no significant difference in the level of protein expression or localization, between wild type and p.Y1347C.
ConclusionsWe report a DUOX2 mutation-carrying pedigree presenting pseudodominant inheritance of nonautoimmune hypothyroidism. We speculate that the relatively high frequency of DUOX2 mutations could lead to pseudodominant inheritance in Japan.

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個体のヨウ素感受性を規定する遺伝因子の探索

鳴海 覚志, 長谷川 奉延, 阿部 清美, 安達 昌功, 荒田 尚子

成長科学協会研究年報 ((公財)成長科学協会)   ( 38 ) 55 - 56 2015.08

ISSN  0386-7617

Severe Osteogenesis Imperfecta Caused by Double Glycine Substitutions Near the Amino-Terminal Triple Helical Region in COL1A2

Masaki Takagi, Hiroyuki Shinohara, Satoshi Narumi, Gen Nishimura, Yukihiro Hasegawa, Tomonobu Hasegawa

AMERICAN JOURNAL OF MEDICAL GENETICS PART A (WILEY-BLACKWELL)  167 ( 7 ) 1627 - 31 2015.07

Accepted,  ISSN  1552-4825

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Most cases of osteogenesis imperfecta (OI) are caused by heterozygous mutations in COL1A1 or COL1A2, the genes encoding the two type I procollagen alpha chains, proa1 (I) and proa2 (I). We report on a unique case of severe OI, a long term survivor of lethal type II OI, rather than progressively deforming type III, due to double substitutions of glycine residues in COL1A2 (p.Gly208Glu and p.Gly235Asp), located on the same allele. To the best of our knowledge, this is the first example of a patient with double COL1A2 glycine substitution mutations on the same allele. We show for the first time that double COL1A2 glycine substitution mutations located near the amino-terminal triple helical region, which individually are likely to result in mild OI, cause severe OI in combination. (C) 2015 Wiley Periodicals, Inc.

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新生児マス・スクリーニング検査でみつかったTPO異常症の2例

石津 桂, 森川 俊太郎, 鳴海 覚志, 長谷川 奉延, 田島 敏広

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)  25 ( 2 ) 227 - 227 2015.07

ISSN  0917-3803

先天性甲状腺機能低下症マススクリーニングの現状の問題点と今後の展望 病型診断と遺伝子検査について

鳴海 覚志, 阿部 清美, 室谷 浩二, 朝倉 由美, 安達 昌功, 長谷川 奉延

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)  25 ( 2 ) 164 - 164 2015.07

ISSN  0917-3803

A case with neonatal hyperinsulinemic hypoglycemia: It is a characteristic complication of sotos syndrome

Yoshie Nakamura, Masaki Takagi, Hiroshi Yoshihashi, Masaru Miura, Satoshi Narumi, Tomonobu Hasegawa, Yoshishige Miyake, Yukihiro Hasegawa

American Journal of Medical Genetics, Part A (Wiley-Liss Inc.)  167 ( 5 ) 1171 - 1174 2015.05

Accepted,  ISSN  1552-4833

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Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis.

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T4補充療法中の先天性甲状腺機能低下症患者におけるFT3、FT4、FT3/FT4比病型別検討

阿部 清美, 鳴海 覚志, 石井 智弘, 井ノ口 美香子, 天野 直子, 柴田 浩憲, 安達 昌功, 室谷 浩二, 朝倉 由美, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  91 ( 1 ) 307 - 307 2015.04

ISSN  0029-0661

生化学的評価で原因特定が困難な原発性副腎機能低下症における包括的遺伝子解析

天野 直子, 鳴海 覚志, 林 美恵, 蜂屋 瑠見, 佐々木 悟郎, 本間 桂子, 石井 智弘, 長谷川 奉延

日本内分泌学会雑誌 ((一社)日本内分泌学会)  91 ( 1 ) 290 - 290 2015.04

ISSN  0029-0661

一過性甲状腺機能低下症の同朋発生により判明したDUOX2異常症の1家系

西門 優一, 井澤 雅子, 濱島 崇, 阿部 清美, 鳴海 覚志, 長谷川 奉延

日本小児科学会雑誌 ((公社)日本小児科学会)  119 ( 3 ) 652 - 652 2015.03

ISSN  0001-6543

Congenital hypothyroidism due to PAX8 mutations

Satoshi Narumi, Tomonobu Hasegawa

Thyroid Diseases in Childhood: Recent Advances from Basic Science to Clinical Practice (Springer International Publishing)     65 - 74 2015.01

Accepted

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PAX8 is one of the best characterized thyroid-specific transcription factors that play a role in development and physiology of the thyroid gland. PAX8 causes, when mutated, congenital hypothyroidism in both mice and humans, although mode of inheritance is different among the two species (mice, recessive
humans, dominant). Genetically engineered PAX8-deficient mice show abnormalities in early proliferation of thyroid precursor cells, resulting in markedly severe thyroid hypoplasia. In humans, clinical phenotypes of mutation carriers are highly variable, ranging from severe congenital hypothyroidism with thyroid hypoplasia to normal thyroid function with a morphologically normal gland. Several genetic epidemiology studies have revealed that PAX8 mutation is a relatively rare cause of human congenital hypothyroidism, observed in about 2 % of cases. Nonetheless, PAX8 mutation is the leading genetic cause of congenital hypothyroidism showing dominant inheritance. Thus, clinicians should consider PAX8 mutations when he/she encounters a patient with positive family history of congenital hypothyroidism. This review focuses on the molecular genetics of human congenital hypothyroidism due to PAX8 mutations.

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Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation

Yumi Asakura, Koji Muroya, Junko Hanakawa, Takeshi Sato, Noriko Aida, Satoshi Narumi, Tomonobu Hasegawa, Masanori Adachi

Clinical Pediatric Endocrinology (Jeff Corporation Co. Ltd)  24 ( 1 ) 27 - 32 2015.01

Accepted,  ISSN  0918-5739

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Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C&gt
T
p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient’s mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD.

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Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

Yumi Asakura, Kiyomi Abe, Koji Muroya, Junko Hanakawa, Yuji Oto, Satoshi Narumi, Tomonobu Hasegawa, Masanori Adachi

HORMONE RESEARCH IN PAEDIATRICS (KARGER)  84 ( 5 ) 349 - 354 2015

Accepted,  ISSN  1663-2818

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Background: Recent reports have indicated that loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1, OMIM 300888) cause congenital central hypothyroidism with macroorchidism. Methods: We conducted a next-generation sequencing-based comprehensive mutation screening for pituitary hormone deficiencies to elucidate molecular mechanisms other than anatomical abnormalities of the pituitary that might be responsible for multiple anterior hormone deficiency in a male patient who originally visited our institute complaining of short stature. He was born large for gestational age (4,370 g, + 3.0 SD) after an obstructed labour. Endocrinological evaluation revealed growth hormone and thyroid-stimulating hormone deficiency. Magnetic resonance imaging showed a discontinuity of the pituitary stalk with an ectopic posterior lobe and a hypoplastic anterior lobe, likely explaining multiple anterior pituitary hormone deficiency. Result: We identified a novel hemizygous IGSF1 mutation (c.1137_1138delCA, p.Asn380Glnfs*6) in the patient. In reviewing the literature, we noticed that all reported Japanese male IGSF1 mutation carriers were born larger than mean standards for gestational age (mean birth weight SD score of +2.0, 95% confidence interval 1.0-3.0). Conclusion: This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation. (C) 2015 S. Karger AG, Basel

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