研究者詳細 - 鳴海　覚志

論文 - 鳴海　覚志

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Fetal Goitrous Hypothyroidism and Polyhydramnios in a Patient with Compound Heterozygous DUOXA2 Mutations.

Tanase-Nakao K, Miyata I, Terauchi A, Saito M, Wada S, Hasegawa T, Narumi S

Hormone research in paediatrics 90 （ 2 ） 132 - 137 2018年

査読有り, ISSN 1663-2818

BACKGROUND: Fetal goiter is only rarely observed in pregnant women without autoimmune thyroid disorders, and there is no epidemiological data on its pathophysiology. Dual oxidase maturation factor 2 (DUOXA2), together with dual oxidase 2, serves pivotal roles in thyroid hormone biosynthesis. To date, all reported patients with DUOXA2 mutations were diagnosed postnatally through newborn screening for congenital hypothyroidism. CASE REPORT: The mother of a male fetus presented at 33 + 4 gestational weeks (GW) with a fetal goiter and polyhydramnios. Cordocentesis revealed fetal hypothyroidism (TSH 253.4 mU/L, FT4 0.29 ng/dL). Intra-amniotic levothyroxine injections were performed at GW 34 + 3 and 35 + 3. The patient was born after spontaneous vaginal delivery at 35 + 6 GW without obstetrical complications. He was treated with levothyroxine until the age of 6 years when reevaluation of his thyroid functions showed normal results (TSH 1.32 mU/L, FT4 1.81 ng/dL). Eleven causative genes of CH, including DUOXA2, were analyzed with use of a next-generation sequencing technique. RESULTS: A next-generation sequencing-based mutation screen led us to find that he was compound heterozygous for 2 previously reported nonsense DUOXA2 mutations (p.[Tyr138*];[Tyr246*]). CONCLUSION: The present case not only illustrates the phenotypic diversity of DUOXA2 mutation carriers but also implies that DUOXA2 is important in prenatal thyroid hormone production.

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Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica.

Takeda R, Takagi M, Shinohara H, Futagawa H, Narumi S, Hasegawa T, Nishimura G, Yoshihashi H

European journal of medical genetics （ELSEVIER SCIENCE BV） 60 （ 12 ） 635 - 638 2017年12月

査読有り, ISSN 1769-7212

Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient.
The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p. Arg60* and p. Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans. (C) 2017 Elsevier Masson SAS. All rights reserved.

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PTEN胚細胞変異を同定した4歳発症の機能性甲状腺結節の1例

長崎啓祐, 入月浩美, 鳴海覚志, 小飼貴彦, 菱沼昭

日本内分泌学会雑誌（(一社)日本内分泌学会） 93 （ 4 ） 1126 - 1126 2017年12月

ISSN 0029-0661

Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity.

Narumi S, Fox LA, Fukudome K, Sakaguchi Z, Sugisawa C, Abe K, Kameyama K, Hasegawa T

Endocrine journal （JAPAN ENDOCRINE SOC） 64 （ 11 ） 1087 - 1097 2017年11月

査読有り, ISSN 0918-8959

Thyroid peroxidase (TPO) deficiency, caused by biallelic TPO mutations, is a well-established genetic form of congenital hypothyroidism (CH). More than 100 patients have been published, and the patients have been diagnosed mostly in the frame of newborn screening (NBS) programs. Correlation between clinical phenotypes and TPO activity remains unclear. Here, we report clinical and molecular findings of two unrelated TPO mutation-carrying mildly hypothyroid patients. The two patients were born at term after an uneventful pregnancy and delivery, and were NBS negative. They sought medical attention due to goiter at age 8 years. Evaluation of the thyroid showed mild elevation of serum TSH levels, normal or slightly low serum T-4 levels, high serum T-3 to T-4 molar ratio, high serum thyroglobulin levels, and high thyroidal I-123 uptake. We performed next-generation sequencing-based genetic screening, and found that one patient was compound heterozygous for two novel TPO mutations (p.Asp224del; c.820-2A>G), and the other was homozygous for a previously known mutation (p.Trp527Cys). In vitro functional analyses using HEK293 cells showed that the two amino acid-altering mutations (p.Asp224del and p.Trp527Cys) caused partial loss of the enzymatic activity. In conclusion, we report that TPO mutations with residual activity are associated with mild TPO deficiency, which is clinically characterized by marked goiter, mild TSH elevation, high serum T-3 to T-4 molar ratio, and high serum thyroglobulin levels. Our findings illuminate the hitherto under-recognized correlation between clinical phenotypes and residual enzymatic activity among patients with TPO deficiency.

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Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature.

Hattori A, Katoh-Fukui Y, Nakamura A, Matsubara K, Kamimaki T, Tanaka H, Dateki S, Adachi M, Muroya K, Yoshida S, Ida S, Mitani M, Nagasaki K, Ogata T, Suzuki E, Hata K, Nakabayashi K, Matsubara Y, Narumi S, Tanaka T, Fukami M

Endocrine journal 64 （ 10 ） 947 - 954 2017年10月

査読有り, ISSN 0918-8959

Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

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Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty

Maki Fukami, Erina Suzuki, Yoko Izumi, Tomohiro Torii, Satoshi Narumi, Maki Igarashi, Mami Miyado, Momori Katsumi, Yasuko Fujisawa, Kazuhiko Nakabayashi, Kenichiro Hata, Akihiro Umezawa, Yoichi Matsubara, Junji Yamauchi, Tsutomu Ogata

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE （WILEY） 21 （ 10 ） 2623 - 2626 2017年10月

査読有り, ISSN 1582-4934

The human genome encodes -750 G-protein-coupled receptors (GPCRs), including prokineticin receptor 2 (PROKR2) involved in the regulation of sexual maturation. Previously reported pathogenic gain-of-function mutations of GPCR genes invariably encoded aberrant receptors with excessive signal transduction activity. Although in vitro assays demonstrated that an artificially created inactive mutant of PROKR2 exerted paradoxical gain-of-function effects when co-transfected with wild-type proteins, such a phenomenon has not been observed in vivo. Here, we report a heterozygous frameshift mutation of PROKR2 identified in a 3.5-year-old girl with central precocious puberty. The mutant mRNA escaped nonsense-mediated decay and generated a GPCR lacking two transmembrane domains and the carboxyl-terminal tail. The mutant protein had no in vitro signal transduction activity; however, cells co-expressing the mutant and wild-type PROKR2 exhibited markedly exaggerated ligand-induced Ca2+ responses. The results indicate that certain inactive PROKR2 mutants can cause early puberty by enhancing the functional property of coexisting wild-type proteins. Considering the structural similarity among GPCRs, this paradoxical gain-of-function mechanism may underlie various human disorders.

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Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty.

Fukami M, Suzuki E, Izumi Y, Torii T, Narumi S, Igarashi M, Miyado M, Katsumi M, Fujisawa Y, Nakabayashi K, Hata K, Umezawa A, Matsubara Y, Yamauchi J, Ogata T

Journal of cellular and molecular medicine 21 （ 10 ） 2623 - 2626 2017年10月

ISSN 1582-1838

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Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty.

Journal of cellular and molecular medicine （Wiley-Blackwell） 21 （ 10 ） 2623 - 2626 2017年10月

査読有り, ISSN 1582-1838

The human genome encodes ~750 G-protein-coupled receptors (GPCRs), including prokineticin receptor 2 (PROKR2) involved in the regulation of sexual maturation. Previously reported pathogenic gain-of-function mutations of GPCR genes invariably encoded aberrant receptors with excessive signal transduction activity. Although in vitro assays demonstrated that an artificially created inactive mutant of PROKR2 exerted paradoxical gain-of-function effects when co-transfected with wild-type proteins, such a phenomenon has not been observed in vivo. Here, we report a heterozygous frameshift mutation of PROKR2 identified in a 3.5-year-old girl with central precocious puberty. The mutant mRNA escaped nonsense-mediated decay and generated a GPCR lacking two transmembrane domains and the carboxyl-terminal tail. The mutant protein had no in vitro signal transduction activity; however, cells co-expressing the mutant and wild-type PROKR2 exhibited markedly exaggerated ligand-induced Ca2+ responses. The results indicate that certain inactive PROKR2 mutants can cause early puberty by enhancing the functional property of coexisting wild-type proteins. Considering the structural similarity among GPCRs, this paradoxical gain-of-function mechanism may underlie various human disorders.

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Homozygous DUOXA2 mutation (p.Tyr138(*)) in a girl with congenital hypothyroidism and her apparently unaffected brother: Case report and review of the literature.

Sugisawa C, Higuchi S, Takagi M, Hasegawa Y, Taniyama M, Abe K, Hasegawa T, Narumi S

Endocrine journal （JAPAN ENDOCRINE SOC） 64 （ 8 ） 807 - 812 2017年08月

査読有り, ISSN 0918-8959

Mutations in DUOXA2, encoding dual oxidase maturation factor 2, is a rare genetic cause of congenital hypothyroidism. Only four biallelic DUOXA2 mutation carriers have been described to date. This study was conducted to report the clinical and genetic findings of a DUOXA2 mutation-carrying family, and to review the previously reported cases. The proband was a 4-year-old girl, who was diagnosed as having congenital hypothyroidism in the frame of newborn screening. She had a high serum TSH level (138 mU/L) and a low free T4 level (0.4 ng/dL). Ultrasonography revealed goiter. She was immediately treated with levothyroxine. At age 3 years, reevaluation of her thyroid function showed a slightly elevated serum TSH level (11.0 mU/L) with normal free T4 level. Screening of the eleven congenital hypothyroidism-related genes demonstrated a previously reported nonsense DUOXA2 mutation (p.Tyr138*) in the homozygous state. Unexpectedly, we also found that the elder brother of the proband, who had no significant past medical history, had the identical homozygous mutation. Using expression experiments with HEK293 cells, we confirmed that p. Tyr138* was a loss-of-function mutation. In the literature, clinical courses of three patients were described, showing characteristic age-dependent improvement of the thyroid function. In conclusion, The proband showed comparable clinical phenotype to previously reported cases, while her brother was unaffected. The phenotypic spectrum of DUOXA2 mutations could be broader than currently accepted.

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SOX2 nonsense mutation in a patient clinically diagnosed with non-syndromic hypogonadotropic hypogonadism.

Shima H, Ishii A, Wada Y, Kizawa J, Yokoi T, Azuma N, Matsubara Y, Suzuki E, Nakamura A, Narumi S, Fukami M

Endocrine journal （JAPAN ENDOCRINE SOC） 64 （ 8 ） 813 - 817 2017年08月

査読有り, ISSN 0918-8959

Hypogonadotropic hypogonadism (HH) is a genetically heterogeneous condition that occurs either as an isolated disorder or as a component of congenital malformation syndromes. SOX2 is a causative gene of syndromic HH characterized by anophthalmia, microphthalmia, or coloboma and other neurological defects such as epilepsy. To date, the causal relationship between SOX2 abnormalities and non-syndromic HH remains speculative. Here, we identified a nonsense mutation of SOX2 in a male patient clinically diagnosed with non-syndromic HH. The patient had epilepsy but no additional clinical features. Ophthalmological examination revealed no abnormalities except for decreased thickness of the retinal nerve fiber layer. Audiometry showed mild sensorineural hearing impairment of both ears. Hormonal evaluation suggested isolated gonadotropin deficiency. Next-generation sequencing-based mutation screening of 13 major causative genes for HH identified a p.Lys35* mutation in SOX2 and excluded pathogenic mutations in other tested genes. The p.Lys35* mutation appeared to encode a non-functioning SOX2 protein that lacks 283 of 317 amino acids. The SOX2 mutation was absent in the maternal DNA sample, while a paternal sample was unavailable for sequence analysis. These results expand the clinical consequences of SOX2 haploinsufficiency to include non-syndromic HH. Systematic mutation screening using a next-generation sequencer and detailed evaluation of nonspecific ocular/neurological features may help identify SOX2 mutation-positive individuals among HH patients.

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Genetic defects in pediatric-onset adrenal insufficiency in Japan.

Amano N, Narumi S, Hayashi M, Takagi M, Imai K, Nakamura T, Hachiya R, Sasaki G, Homma K, Ishii T, Hasegawa T

European journal of endocrinology 177 （ 2 ） 187 - 194 2017年08月

査読有り, ISSN 0804-4643

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部分型TPO異常症新生児マススクリーニングが陰性であったTPO変異の2例

鳴海覚志, 阿部清美, Fox Larry A., 福留啓祐, 坂口善市, 深見真紀, 長谷川奉延

日本内分泌学会雑誌（(一社)日本内分泌学会） 93 （ 1 ） 261 - 261 2017年04月

ISSN 0029-0661

A novel de novo germline mutation Glu40Lys in AKT3 causes megalencephaly with growth hormone deficiency.

Takagi M, Dobashi K, Nagahara K, Kato M, Nishimura G, Fukuzawa R, Narumi S, Hasegawa T

American journal of medical genetics. Part A （WILEY） 173 （ 4 ） 1071 - 1076 2017年04月

査読有り, ISSN 1552-4825

Germline or somatic gain-of-function mutations in the v-akt murine thymoma viral oncogene homolog 3 (AKT3) have been reported to cause syndromic megalencephaly. We describe a novel germline mutation, p.Glu40Lys, in AKT3. Phenotypically, the patient presented with megalencephaly with hypotonia, apparent connective tissue laxity, and growth hormone (GH) deficiency. To our knowledge, this is the first instance of a patient with megalencephaly with GH deficiency, harboring a germline de novo mutation in AKT3. (C) 2017 Wiley Periodicals, Inc.

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Luscan-Lumish症候群による巨人症の機序の解析

隅田健太郎, 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, 西澤衡, 高橋路子, 鳴海覚志, 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） 93 （ 1 ） 263 - 263 2017年04月

ISSN 0029-0661

同胞間で異なる経過をたどる先天性甲状腺機能低下症病型診断結果と遺伝子診断結果

小泉美紀子, 川井正信, 大沼真輔, 中長摩利子, 庄司保子, 阿部清美, 佐藤武志, 鳴海覚志, 長谷川奉延, 惠谷ゆり, 位田忍

日本内分泌学会雑誌（(一社)日本内分泌学会） 93 （ 1 ） 343 - 343 2017年04月

ISSN 0029-0661

新規遺伝子変異を同定したアンドロゲン不応症の1例

岩橋めぐみ, 小澤綾子, 佐藤武志, 鳴海覚志, 長谷川奉延, 宮田市郎

日本内分泌学会雑誌（(一社)日本内分泌学会） 93 （ 1 ） 381 - 381 2017年04月

ISSN 0029-0661

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年04月

ISSN 0029-0661

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

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

Endocrine journal （JAPAN ENDOCRINE SOC） 64 （ 2 ） 229 - 234 2017年02月

査読有り, 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年01月

ISSN 0029-0661

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

Suzuki E, Bo R, Sue K, Awano H, Ogata T, Narumi S, Kagami M, Sano S, Fukami M

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

査読有り, 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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