論文 - 鳴海　覚志

次世代シーケンシングによる先天性甲状腺機能低下症の包括的遺伝子解析

鳴海 覚志, 阿部 清美, 天野 直子, 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）  88 （ 2 ） 498 - 498 2012年09月

ISSN  0029-0661

先天性甲状腺機能低下症発症におけるPathway Burden仮説の提唱

阿部 清美, 鳴海 覚志, 天野 直子, 石井 智弘, 室谷 浩二, 朝倉 由美, 安達 昌功, 佐々木 悟郎, 長崎 啓祐, 阿部 貴行, 長谷川 奉延

日本内分泌学会雑誌 （(一社)日本内分泌学会）  88 （ 2 ） 543 - 543 2012年09月

ISSN  0029-0661

Acceleration of diabetes development in CXC chemokine receptor 3 (CXCR3)-deficient NOD mice.

Yamada Y, Okubo Y, Shimada A, Oikawa Y, Yamada S, Narumi S, Matsushima K, Itoh H

Diabetologia 55 （ 8 ） 2238 - 45 2012年08月

ISSN  0012-186X

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新生児マス・スクリーニングの震災対応はどうあるべきか 東日本大震災1年を経過して 東日本大震災が新生児マス・スクリーニングシステムに及ぼした影響 内分泌疾患を中心に

南谷 幹史, 皆川 真規, 伊藤 順庸, 鬼形 和道, 鈴木 順造, 高橋 明雄, 長崎 啓祐, 鳴海 覚志, 難波 範行, 原田 正平, 藤原 幾磨, 堀川 玲子, 水野 晴夫, 横谷 進

日本マス・スクリーニング学会誌 （日本マススクリーニング学会）  22 （ 2 ） 158 - 158 2012年07月

ISSN  0917-3803

東日本大震災の新生児マススクリーニングに対する影響調査

南谷 幹史, 皆川 真規, 伊藤 順庸, 鬼形 和道, 鈴木 順造, 高橋 明雄, 長崎 啓祐, 鳴海 覚志, 難波 範行, 原田 正平, 藤原 幾磨, 堀川 玲子, 水野 晴夫, 横谷 進

日本内分泌学会雑誌 （(一社)日本内分泌学会）  88 （ 1 ） 308 - 308 2012年04月

ISSN  0029-0661

東日本大震災の新生児マス・スクリーニングに対する影響調査

南谷 幹史, 皆川 真規, 鈴木 順造, 高橋 明雄, 長崎 啓祐, 鳴海 覚志, 原田 正平, 藤原 幾磨, 堀川 玲子, 横谷 進, 日本小児内分泌学会震災小児甲状腺PT

日本小児科学会雑誌 （(公社)日本小児科学会）  116 （ 2 ） 278 - 278 2012年02月

ISSN  0001-6543

A family of pseudohypoparathyroidism type Ia with an 850-kb submicroscopic deletion encompassing the whole GNAS locus.

Mitsui T, Nagasaki K, Takagi M, Narumi S, Ishii T, Hasegawa T

American journal of medical genetics. Part A （WILEY-BLACKWELL）  158A （ 1 ） 261 - 4 2012年01月

査読有り,  ISSN  1552-4825

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Gradual loss of ACTH due to a novel mutation in LHX4: comprehensive mutation screening in Japanese patients with congenital hypopituitarism.

Takagi M, Ishii T, Inokuchi M, Amano N, Narumi S, Asakura Y, Muroya K, Hasegawa Y, Adachi M, Hasegawa T

PloS one （PUBLIC LIBRARY SCIENCE）  7 （ 9 ） e46008 2012年

査読有り,  ISSN  1932-6203

　概要を見る

Mutations in transcription factors genes, which are well regulated spatially and temporally in the pituitary gland, result in congenital hypopituitarism (CH) in humans. The prevalence of CH attributable to transcription factor mutations appears to be rare and varies among populations. This study aimed to define the prevalence of CH in terms of nine CH-associated genes among Japanese patients. We enrolled 91 Japanese CH patients for DNA sequencing of POU1F1, PROP1, HESX1, LHX3, LHX4, SOX2, SOX3, OTX2, and GLI2. Additionally, gene copy numbers for POU1F1, PROP1, HESX1, LHX3, and LHX4 were examined by multiplex ligation-dependent probe amplification. The gene regulatory properties of mutant LHX4 proteins were characterized in vitro. We identified two novel heterozygous LHX4 mutations, namely c.249-1G>A, p.V75I, and one common POU1F1 mutation, p.R271W. The patient harboring the c.249-1G>A mutation exhibited isolated growth hormone deficiency at diagnosis and a gradual loss of ACTH, whereas the patient with the p.V75I mutation exhibited multiple pituitary hormone deficiency. In vitro experiments showed that both LHX4 mutations were associated with an impairment of the transactivation capacities of POU1F1 and alpha GSU, without any dominant-negative effects. The total mutation prevalence in Japanese CH patients was 3.3%. This study is the first to describe, a gradual loss of ACTH in a patient carrying an LHX4 mutation. Careful monitoring of hypothalamic-pituitary -adrenal function is recommended for CH patients with LHX4 mutations.

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【小児内分泌学の進歩2012】骨代謝・副甲状腺 GNAS変異陰性-偽性副甲状腺機能低下症IaにおけるGNAS遺伝子領域の全てを含む欠失の同定

三井 俊賢, 長崎 啓祐, 高木 優樹, 鳴海 覚志, 石井 智弘, 長谷川 奉延

ホルモンと臨床 （(有)医学の世界社）  59 （ 12 ） 1085 - 1087 2011年12月

ISSN  0045-7167

非古典型TSH不応症 奇異性123I摂取率高値を特徴とする先天性甲状腺機能低下症の新しい病型の提唱

鳴海 覚志, 長崎 啓祐, 石井 智弘, 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）  87 （ 2 ） 516 - 516 2011年09月

ISSN  0029-0661

DUOX2変異による偽性優性遺伝を示した先天性甲状腺機能低下症の一家系

阿部 清美, 濱島 崇, 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）  87 （ 2 ） 509 - 509 2011年09月

ISSN  0029-0661

A new rapid protocol for eyeblink conditioning to assess cerebellar motor learning.

Emi K, Kohda K, Kakegawa W, Narumi S, Yuzaki M

Neurochemical research 36 （ 7 ） 1314 - 22 2011年07月

ISSN  0364-3190

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当院で経験した自律性機能性甲状腺結節(AFTN)の1男児例

神原 亜紀子, 小山 さとみ, 志村 直人, 鳴海 覚志, 長谷川 奉延, 有阪 治

日本小児科学会雑誌 （(公社)日本小児科学会）  115 （ 2 ） 434 - 434 2011年02月

ISSN  0001-6543

一過性甲状腺機能低下症におけるDUOX2遺伝子解析の検討

長崎 啓祐, 鳴海 覚志, 小川 洋平, 菊池 透, 浅見 直, 長谷川 奉延, 内山 聖

日本内分泌学会雑誌 （(一社)日本内分泌学会）  86 （ 2 ） 266 - 266 2010年09月

ISSN  0029-0661

甲状腺形成異常におけるCopy number variation異常解析

鳴海 覚志, 室谷 浩二, 朝倉 由美, 安達 昌功, 長崎 啓祐, 天野 直子, 石井 智弘, 石井 美穂, 江見 充, 長谷川 奉延

日本内分泌学会雑誌 （(一社)日本内分泌学会）  86 （ 2 ） 267 - 267 2010年09月

ISSN  0029-0661

One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based Computational Mutation Prediction.

Narumi S, Cho H, Tamada I, Kozu Y, Tsuchiya T, Nagai T, Hasegawa T

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 19 （ 4 ） 91-99 - 9 2010年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0918-5739

　概要を見る

Inactivating mutations of THRB, which encodes the thyroid hormone receptor β (TRβ), cause resistance to thyroid hormone (RTH
OMIM 190160). To date, more than 100 THRB mutations have been reported among RTH patients. Most mutations substitute a single amino-acid residue in the ligand-binding domain. In this report, we describe clinical and molecular findings of three families with RTH. Three families harbored one novel (p.I431M) and two recurrent (p.R320H and p.R383C) THRB mutations. To examine the pathogenicity of identified mutations, we introduced a novel computational mutation prediction method based on three-dimensional structure data of TRβ-T3 complex. First, to define the accuracy of our prediction system, we evaluated ten previously reported 'positive control' mutations, as well as 30 seemingly benign sequence variations observed among vertebral species as 'negative controls'. We found that our system had a sensitivity of 80% and a specificity of 93%. We then analyzed three mutations detected in the present study and found that all three mutations are predicted to be deleterious. Our data suggest that our structure-based prediction system would be a prompt, inexpensive and feasible method for evaluating the pathogenicity of missense THRB mutations. © 2010 by The Japanese Society for Pediatric Endocrinology.

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A patient with Pendred syndrome whose goiter progressed with normal serum thyrotropin and iodine organification

Asakura Y, Narumi S, Muroya K, Fujita K, Aida N, Hasagawa T, Adachi M.

American Journal of Medical Genetics Part A （WILEY-LISS）  152A （ 7 ） 1793-1797 - 1797 2010年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1552-4825

　概要を見る

Biallelic mutations of SLC26A4 (encoding pendrin) cause Pendred syndrome (PS), an autosomal recessive genetic disorder with deafness and goiter. The mechanism underlying the development of the goiter is unknown. Here, we report clinical and molecular findings of a patient with PS. This 27-year-old woman was born to nonconsanguineous healthy parents. She was seen at our hospital due to hearing loss at age 3 years, and subsequently developed goiter at age 10 years. From age 15 years, her thyroid gland showed progressive enlargement accompanied by elevation of serum thyroglobulin reaching 10-fold the normal amount. Thyroidal iodine uptake was also increased during goiter progression ((123)I uptake at 24 hr: 20.2% at age 17 years; 69.4% at age 24 years; reference, 8-40), while serum thyrotropin (TSH) levels and iodine organification (examined by the per-chrolate or thiocyanate discharge test) remained normal. We sequenced SLC26A4 using standard PCR-based technique, and found one novel (p.T537P) and one recurrent (p.H723R) mutations in a compound heterozygous state. Expression experiments using COS-7 cells showed that the two mutants were entrapped in the endoplasmic reticulum and were poorly localized at the plasma membrane. In summary, a molecularly confirmed PS patient showed goiter progression accompanied by elevated serum thyroglobulin and increased thyroidal iodine uptake, but normal serum TSH levels and normal iodine organification. This implies that some pendrin mutations may involve direct stimulation of thyroid cell proliferation with no TSH hyperstimulation and no iodine organification defect. (C) 2010 Wiley-Liss, Inc.

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Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer.

Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R, Watanabe M, Yuzaki M

Science (New York, N.Y.) 328 （ 5976 ） 363 - 8 2010年04月

ISSN  0036-8075

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Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients.

Narumi S, Muroya K, Asakura Y, Adachi M, Hasegawa T

The Journal of clinical endocrinology and metabolism （ENDOCRINE SOC）  95 （ 4 ） 1981-1985 - 5 2010年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0021-972X

　概要を見る

Context: Gene mutations of transcription factors that are predominantly expressed in the thyroid gland cause congenital hypothyroidism (CH). The prevalence of CH due to transcription factor mutations remains undetermined.
Objective: This study was designed to define the prevalence of CH due to mutations of PAX8, NKX2-1 [encoding thyroid transcription factor (TTF)-1], FOXE1 (encoding TTF-2), and NKX2-5 among patients with permanent primary CH and in the general population in Japan.
Subjects and Methods: We enrolled 102 CH patients that represent 353,000 newborns born in Kanagawa prefecture from October 1979 to June 2006. We sequenced PAX8, NKX2-1, FOXE1, and NKX2-5 using PCR-based methods. Additionally, deletion/duplication of PAX8, NKX2-1, and FOXE1 was screened by multiplex ligation-dependent probe amplification. Molecular functions of putative mutations were verified in vitro.
Results: We identified a novel small duplication of PAX8 (p.K80_A84dup) in two half-sibling patients with thyroid hypoplasia. We also found a novel NKX2-1 variation (p.H60W) in a sporadic nonsyndromic CH patient. In vitro experiments showed that K80_A84dup PAX8 had impaired transactivation of the thyroglobulin promoter. H60W TTF-1 exhibited a comparable transactivating capacity with wild-type TTF-1, suggesting a benign variation. We estimate the prevalence of PAX8 mutations to be 2.0% (two in 102) among Japanese CH patients and one in 176,000 (two in 353,000) in the general Japanese population.
Conclusions: Using a population-based sample, we confirmed that a minor subset of CH patients has transcription factor mutations, but they are rare. In our cohort, PAX8 mutations were the leading cause of such a rare condition. (J Clin Endocrinol Metab 95: 1981-1985, 2010)

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Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray.

Narumi S, Numakura C, Shiihara T, Seiwa C, Nozaki Y, Yamagata T, Momoi MY, Watanabe Y, Yoshino M, Matsuishi T, Nishi E, Kawame H, Akahane T, Nishimura G, Emi M, Hasegawa T

American journal of medical genetics. Part A （WILEY-LISS）  152A （ 1 ） 133-140 - 40 2010年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1552-4825

　概要を見る

Osteoporosis-pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal-recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early-onset visual disturbance, with or without mental retardation. We undertook standard PCR-based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT-PCR from lymphocytic RNA demonstrated splice error resulting in 63-bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT-PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom-designed oligonucleotide tiling microarray analyses targeted to a 600-kb genome region harboring LRP5 and discovered a 7.2-kb microdeletion encompassing exons 22 and 23 of LRP5. We found various types of LRP5 mutations, including an exon-level deletion that is undetectable by standard PCR-based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations. (C) 2009 Wiley-Liss, Inc.

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