論文 - 鳴海　覚志

Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice.

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

PloS one 11 （ 11 ） e0166144 2016年

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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年11月

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年11月

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年09月

ISSN  2189-7549

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

Abe K, Narumi S, Suwanai AS, Hamajima T, Hasegawa T

Clinical endocrinology （WILEY-BLACKWELL）  83 （ 3 ） 394 - 8 2015年09月

査読有り,  ISSN  0300-0664

　概要を見る

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年08月

ISSN  0386-7617

Severe osteogenesis imperfecta caused by double glycine substitutions near the amino-terminal triple helical region in COL1A2.

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

American journal of medical genetics. Part A （WILEY-BLACKWELL）  167 （ 7 ） 1627 - 31 2015年07月

査読有り,  ISSN  1552-4825

　概要を見る

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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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年07月

ISSN  0917-3803

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年07月

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年05月

査読有り,  ISSN  1552-4833

　概要を見る

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年04月

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年04月

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年03月

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年01月

査読有り

　概要を見る

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.

Asakura Y, Muroya K, Hanakawa J, Sato T, Aida N, Narumi S, Hasegawa T, Adachi M

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology （Jeff Corporation Co. Ltd）  24 （ 1 ） 27 - 32 2015年01月

査読有り,  ISSN  0918-5739

　概要を見る

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年

査読有り,  ISSN  1663-2818

　概要を見る

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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Human Chorionic Gonadotropin Stimulation Test in Prepubertal Children with Micropenis Can Accurately Predict Leydig Cell Function in Pubertal or Postpubertal Adolescents.

Ishii T, Matsuo N, Sato S, Ogata T, Tamai S, Anzo M, Kamimaki T, Sasaki G, Inokuchi M, Hori N, Amano N, Narumi S, Shibata H, Hasegawa T

Hormone research in paediatrics （KARGER）  84 （ 5 ） 305 - 10 2015年

査読有り,  ISSN  1663-2818

　概要を見る

Background/Aim: To evaluate the accuracy of the human chorionic gonadotropin (hCG) stimulation test in children with micropenis in predicting later Leydig cell function. Methods: We conducted a retrospective investigation of testosterone response to a 3-day hCG test (3,000 IU/m(2)/day) in prepuberty to indicate the need for hormone replacement therapy (HRT) in adolescence. Results: Fifty Japanese boys (range, 0.8-15.4 years of age; median, 8.9) with micropenis were enrolled. Thirty-four spontaneously developed puberty and preserved the ability of testosterone production (group 1), while 16 did not develop any pubertal signs without HRT (group 2). Serum testosterone levels after the hCG test (post-hCG T) in group 2 (range, <0.05-1.1 ng/ml; median, 0.24) were significantly lower than in group 1 (range, 0.5-8.7 ng/ml; median, 2.4; p < 0.0001). Based on true positives who required continuous HRT, the area under the receiver-operating characteristics curve for post-hCG T was 0.983 [95% confidence interval (CI), 0.90-1.00]. The post-hCG T cut-off level corresponding to the Youden index was 1.1 ng/ml (95% CI, 1.0-1.1), with a sensitivity of 100.0% (95% CI, 79.4-100.0) and a specificity of 94.1% (95% CI, 80.3-99.3). Conclusions: The hCG test in prepubertal children with micropenis can be useful for predicting Leydig cell function in pubertal or postpubertal adolescents. The post-hCG T cutoff level of 1.1 ng/ml is recommended to screen for those who will likely require HRT for pubertal development. (C) 2015 S. Karger AG, Basel

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TSH resistance revisited.

Narumi S, Hasegawa T

Endocrine journal （JAPAN ENDOCRINE SOC）  62 （ 5 ） 393 - 8 2015年

査読有り,  ISSN  0918-8959

　概要を見る

Genetic defects of hormone receptors are the most common form of end-organ hormone resistance. One example of such defects is TSH resistance, which is caused by biallelic inactivating mutations in the TSH receptor gene (TSHR). TSH, a master regulator of thyroid functions, affects virtually all cellular processes involving thyroid hormone production, including thyroidal iodine uptake, thyroglobulin iodination, reuptake of iodinated thyroglobulin and thyroid cell growth. Resistance to TSH results in defective thyroid hormone production from the neonatal period, namely congenital hypothyroidism. Classically, clinical phenotypes of TSH resistance due to inactivating TSHR mutations were thought to vary depending on the residual mutant receptor activity. Nonfunctional mutations in the two alleles produce severe thyroid hypoplasia with overt hypothyroidism (uncompensated TSH resistance), while hypomorphic mutations in at least one allele produce normal-sized thyroid gland with preserved hormone-producing capacity (compensated TSH resistance). More recently, a new subgroup of TSH resistance (nonclassic TSH resistance) that is characterized by paradoxically high thyroidal iodine uptake has been reported. In this article, the pathophysiology and clinical features of TSH resistance due to inactivating TSHR mutations are reviewed, with particular attention to the nonclassic form.

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Comprehensive next-generation sequencing analyses of hypoparathyroidism: identification of novel GCM2 mutations.

Mitsui T, Narumi S, Inokuchi M, Nagasaki K, Nakazawa M, Sasaki G, Hasegawa T

The Journal of clinical endocrinology and metabolism （ENDOCRINE SOC）  99 （ 11 ） E2421 - 8 2014年11月

査読有り,  ISSN  0021-972X

　概要を見る

Context: In most patients with hypoparathyroidism (HP), the etiology is not defined clinically. Eight genes (AIRE, CASR, CLDN16, GATA3, GCM2, PTH, TBCE, and TRPM6) are known to be responsible genes associated with HP; however, no previous study has screened the eight responsible genes comprehensively in HP patients.
Objectives: This study was conducted to determine the genetic defect in HP patients. We also described clinical and molecular findings of two HP patients with novel GCM2 mutations.
Subjects and Methods: We enrolled 20 nonconsanguineous Japanese patients with child-onset permanent HP without 22q11 deletion. Mutations and genomic rearrangements involving the eight genes were screened by targeted next-generation sequencing (NGS). We also screened genetic rearrangements by array comparative genomic hybridization (aCGH) in the mutation-negative patients. A putative deletion, which was suspected by NGS, was additionally analyzed by droplet digital PCR (ddPCR) and junction PCR. Identified novel nucleotide-level GCM2 mutants were characterized in vitro.
Results: We identified seven patients with a single gene disorder, including a CASR mutation, GATA3 mutations, and novel GCM2 mutations (R367Tfs*15, T370M, and the deletion encompassing exon 1). This submicroscopic deletion, which had been suspected by NGS, could not be detected by aCGH and was confirmed by ddPCR and junction PCR. Functional studies of R367Tfs*- and T370M-GCM2 demonstrated a reduction of target gene transactivation in both.
Conclusions: Using comprehensive NGS analyses, we identified the genetic defect in 35% of HP patients in our cohort and discovered novel GCM2 mutations including submicroscopic deletion that was undetectable by aCGH.

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遷延する妊娠甲状腺中毒症に検出されたTSH受容体遺伝子変異

谷山 松雄, 杉澤 千穂, 百渓 尚子, 井上 ゆか子, 阿部 清美, 鳴海 覚志

日本内分泌学会雑誌 （(一社)日本内分泌学会）  90 （ 2 ） 506 - 506 2014年09月

ISSN  0029-0661