山田 茉未子 (ヤマダ マミコ)

Yamada, Mamiko

写真a

所属(所属キャンパス)

医学部 臨床遺伝学センター (信濃町)

職名

助教(有期)

経歴 【 表示 / 非表示

  • 2011年04月
    -
    2013年03月

    慶應義塾大学病院, 初期臨床研修医

  • 2014年04月
    -
    2017年03月

    慶應義塾大学小児科学教室, 助教(専修医)

  • 2017年04月
    -
    2018年03月

    慶應義塾大学小児科学教室, 助教(小児科)

  • 2018年04月
    -
    2019年03月

    慶應義塾大学保健管理センター, 助教

  • 2018年04月
    -
    継続中

    慶應義塾大学医学部臨床遺伝学センター

学歴 【 表示 / 非表示

  • 2005年04月
    -
    2011年03月

    慶應義塾, 医学部

    大学, 卒業

学位 【 表示 / 非表示

  • 博士(医学), 慶應義塾, 論文, 2020年03月

 

論文 【 表示 / 非表示

  • Fork-shaped mandibular incisors as a novel phenotype of LRP5-associated disorder

    Yamada M., Kubota K., Uchida A., Yagihashi T., Kawasaki M., Suzuki H., Uehara T., Takenouchi T., Kurosaka H., Kosaki K.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  185 ( 5 ) 1544 - 1549 2021年05月

    ISSN  15524825

     概要を見る

    The LRP5 gene encodes a Wnt signaling receptor to which Wnt binds directly. In humans, pathogenic monoallelic variants in LRP5 have been associated with increased bone density and exudative vitreoretinopathy. In mice, LRP5 plays a role in tooth development, including periodontal tissue stability and cementum formation. Here, we report a 14-year-old patient with a de novo non-synonymous variant, p.(Val1245Met), in LRP5 who exhibited mildly reduced bone density and mild exudative vitreoretinopathy together with a previously unreported phenotype consisting of dental abnormalities that included fork-like small incisors with short roots and an anterior open bite, molars with a single root, and severe taurodontism. In that exudative vitreoretinopathy has been reported to be associated with heterozygous loss-of-function variants of LRP5 and that our patient reported here with the p.(Val1245Met) variant had mild exudative vitreoretinopathy, the variant can be considered as an incomplete loss-of-function variant. Alternatively, the p.(Val1245Met) variant can be considered as exerting a dominant-negative effect, as no patients with truncating LRP5 variants and exudative vitreoretinopathy have been reported to exhibit dental anomalies. The documentation of dental anomalies in the presently reported patient strongly supports the notion that LRP5 plays a critical role in odontogenesis in humans, similar to its role in mice.

  • Role of chimeric transcript formation in the pathogenesis of birth defects

    Yamada M., Suzuki H., Watanabe A., Uehara T., Takenouchi T., Mizuno S., Kosaki K.

    Congenital Anomalies (Congenital Anomalies)  61 ( 3 ) 76 - 81 2021年05月

    ISSN  09143505

     概要を見る

    Chimeric transcripts are formed by chromosomal aberrations. Little is known about the role of chimeric transcripts in the pathogenesis of birth defects. We reanalyzed RNA-seq data in alignment map files from the peripheral blood of 56 patients in whom the diagnoses could not be confirmed by standard exome analysis and transcriptome analysis to screen for chimeric transcripts using a dedicated software, ChimPipe. Chimeric analysis led to a diagnosis in two of the 56 patients: (a) the first patient had a chimeric transcript spanning the causative gene ZEB2 and the GTDC1 gene in its neighboring locus. RNA-seq revealed reads spanning exon 5 of ZEB2 and exon 7 of GTDC1. Whole genome sequencing revealed a 436-kb deletion spanning intron 4 of ZEB2 and intron 7 of GTDC1 and the diagnosis of Mowat-Wilson syndrome was made. (b) The second patient had a chimeric transcript spanning the causative gene KCNK9 and the TRAPPC9 gene in its neighboring locus. RNA-seq revealed reads spanning exon 21 of TRAPPC9 and exon 1 of KCNK9. Whole genome sequencing revealed a 186-kb deletion spanning intron 20 of TRAPPC9 and intron 1 of KCNK9 in this patient. KCNK9 gene is a maternally expressed imprinted gene. The diagnosis of Birk-Barel syndrome was made. Thus, both patients had chimeric transcripts that were directly involved in the pathogenesis of the birth defects. The approach reported herein, of detecting chimeric transcripts from RNA-seq data, is unique in that the approach does not rely on any prior information on the presence of genomic deletion.

  • Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures

    Suzuki H., Inaba M., Yamada M., Uehara T., Takenouchi T., Mizuno S., Kosaki K., Doi M.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  185 ( 4 ) 1182 - 1186 2021年04月

    ISSN  15524825

     概要を見る

    The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.

  • Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants

    Yamada M., Ono M., Ishii T., Suzuki H., Uehara T., Takenouchi T., Kosaki K.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  2021年

    ISSN  15524825

     概要を見る

    Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing-genes. RNPC3 (RNA-binding domain-containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di-snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non-synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3-related disorders.

  • Ketogenic diet for refractory epilepsy with MEHMO syndrome: Caution for acute necrotizing pancreatitis

    Mori M., Kumada T., Inoue K., Nozaki F., Matsui K., Maruo Y., Yamada M., Suzuki H., Kosaki K., Shibata M.

    Brain and Development (Brain and Development)  2021年

    ISSN  03877604

     概要を見る

    Background: The MEHMO (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity) syndrome, which is caused by a hemizygous variant in the EIF2S3 gene on chromosome Xp22, is associated with significant morbidity and mortality. Refractory epileptic seizures and glucose dysregulation are characteristic manifestations of the MEHMO syndrome, which can often diminish patients’ quality of life. Case: A 5-year-old boy was referred to our hospital because of profound intellectual disability, micropenis, cryptorchidism, central hypothyroidism, and microcephaly. He had neonatal hypoglycemia at birth and later experienced refractory epileptic seizures and developed obesity and insulin-dependent diabetes. A diagnosis of MEHMO syndrome was established on the basis of the patient's clinical manifestations and de novo novel missense variant in the EIF2S3 gene (NM_001415.3:c.805 T > G) that was detected through whole-exome analysis. Although the patient's refractory seizures and diabetes had been well controlled with a combination of ketogenic diet (KD) therapy and insulin therapy, acute fatal necrotizing pancreatitis occurred at the age of 68 months. Moreover, despite intensive care, his condition rapidly deteriorated to multiple organ failure and acute respiratory distress syndrome, resulting in death. Conclusion: The pathophysiology of glucose intolerance in MEHMO syndrome remains to be elucidated; however, recent studies have suggested that EIF2S3 gene variants could lead to glucose dysregulation and β-cell damage in the pancreas. We suspect that in the present case, KD therapy led to an abnormal load on the beta cells that were damaged owing to eIF2γ dysfunction. Therefore, the adverse effects of KD in patients with MEHMO syndrome should be considered.

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総説・解説等 【 表示 / 非表示

研究発表 【 表示 / 非表示

  • Documentation of IFT172 as the nineteenth gene causative of oral-facial-digital syndrome underscores the importance of ciliary trafficking in its pathogenesis.

    2020 Western Medical Research Conference, 2020年01月, 口頭(一般)

  • Integration of exome data with transcriptome data increased detection of pathogenic variants by 20% among 179 samples.

    日本人類遺伝学会第64回大会・東アジア人類遺伝学会連合第19回大会, 2019年11月, 口頭(一般)

  • Effectiveness of integrated interpretation of exome and corresponding transcriptome data in detecting splicing variants: Population and clinical studies

    山田茉未子

    第59回日本先天異常学会・The 13th World Congress of International Cleft Lip and Palate Foundation CLEFT 2019 ICPF合同学術集会, 2019年07月, 口頭(一般)

  • Effectiveness of integrated interpretation of exome and corresponding transcriptome data in detecting splicing variants of recessive disorders

    European Human Genetics Conference, 2019年06月, 口頭(一般)

  • Integrated analysis of RNA-seq and exome data in 179 subjects unravels frequent protein-truncating splicing events out of “missense” or “silent” mutations

    山田 茉未子

    第41回日本小児遺伝学会学術集会, 2019年01月, 口頭(一般)

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競争的資金等の研究課題 【 表示 / 非表示

  • 小児先天性遺伝性疾患における新たな発症機序の解明―ゲノム構造異常によるキメラ遺伝子形成の網羅的解析―

    2020年09月
    -
    2021年03月

    補助金,  代表

  • 哺乳不良を伴う新生児および乳児を対象とした、原因疾患の早期診断のための遺伝学的アプローチ:人工知能によるスプライシング異常の検出およびエクソーム・RNA統合解析の有用性の検討

    2020年04月
    -
    2021年09月

    補助金,  代表

  • 遺伝性疾患の発症機序としてのキメラ遺伝子形成:全ゲノム・RNA 統合解析による検討

    2020年04月
    -
    2021年03月

    補助金,  代表

  • スプライシング変異の転写後配列への影響:ゲノム・トランスクリプトーム統合解析

    2019年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 山田 茉未子, 若手研究, 補助金,  代表

  • 人工知能を用いた原因不明肝臓疾患のスプライシング異常の検出

    2019年04月
    -
    2020年03月

    山田茉未子, ゲノム科学・バイオインフォマティクス, 補助金,  代表

受賞 【 表示 / 非表示

  • The Western society of pediatric research & Mead Johnson Nutrition Award

    2020年01月

    受賞区分: 国際学会・会議・シンポジウム等の賞

  • Gold Award, 13th World Congress of The Intentional Cleft Lip and Palate Foundation CLEFT2019

    2019年07月,  Congress of The Intentional Cleft Lip and Palate Foundation, Effectiveness of integrated interpretation of exome and corresponding transcriptome data in detecting splicing variants: Population and clinical studies

    受賞区分: 国際学会・会議・シンポジウム等の賞

  • 優秀演題賞、日本小児遺伝学会

    2019年01月, 第41回日本小児遺伝学会学術集会, Integrated analysis of RNA-seq and exome data in 179 subjects unravels frequent protein-truncating splicing events out of “missense” or “silent” mutations

    受賞区分: 国内学会・会議・シンポジウム等の賞

 

所属学協会 【 表示 / 非表示

  • 日本小児内分泌学会, 

    2015年
    -
    継続中
  • 日本小児科学会, 

    2013年04月
    -
    継続中
  • 日本人類遺伝学会

     
  • 日本先天異常学会

     
  • 日本学校保健学会

     

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