Yamada, Mamiko

写真a

Affiliation

School of Medicine, Center for Medical Genetics (Shinanomachi)

Position

Instructor

Career 【 Display / hide

  • 2011.04
    -
    2013.03

    慶應義塾大学病院, 初期臨床研修医

  • 2014.04
    -
    2017.03

    Keio University, Department of Pediatrics, 助教(専修医)

  • 2017.04
    -
    2018.03

    Keio University, Department of Pediatrics, 助教(小児科)

  • 2018.04
    -
    2019.03

    Keio University, Health Center, 助教

  • 2018.04
    -
    Present

    慶應義塾大学医学部臨床遺伝学センター

Academic Background 【 Display / hide

  • 2005.04
    -
    2011.03

    Keio University, 医学部

    University, Graduated

Academic Degrees 【 Display / hide

  • 博士(医学), Keio University, Dissertation, 2020.03

 

Papers 【 Display / hide

  • 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 2021.05

    ISSN  09143505

     View Summary

    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.

  • 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 2021.05

    ISSN  15524825

     View Summary

    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.

  • 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 2021.04

    ISSN  15524825

     View Summary

    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.

  • Recurrent NFIA K125E substitution represents a loss-of-function allele: Sensitive in vitro and in vivo assays for nontruncating alleles

    Uehara T., Sanuki R., Ogura Y., Yokoyama A., Yoshida T., Futagawa H., Yoshihashi H., Yamada M., Suzuki H., Takenouchi T., Matsubara K., Hirata H., Kosaki K., Takano-Shimizu T.

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

    ISSN  15524825

     View Summary

    Nuclear factor I A (NFIA) is a transcription factor that belongs to the NFI family. Truncating variants or intragenic deletion of the NFIA gene are known to cause the human neurodevelopmental disorder known as NFIA-related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the NFIA-related disorder who shared a missense variant p.Lys125Glu (K125E) in the NFIA gene. Patient 1 was a 6-year-old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14-month-old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild-type human NFIA in Drosophila caused developmental defects such as eye malformation and premature death, while that of human NFIA K125E variant allele did not. nfia-deficient zebrafish embryos showed defects of midline-crossing axons in the midbrain/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild-type human NFIA, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of HES1 promoter in cultured cells. Taken together, we concluded that the K125E variant in the NFIA gene is a loss-of-function mutation.

  • 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

    ISSN  15524825

     View Summary

    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.

display all >>

Reviews, Commentaries, etc. 【 Display / hide

Presentations 【 Display / hide

  • 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, 2020.01, Oral Presentation(general)

  • 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, 2019.11, Oral Presentation(general)

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

    Mamiko Yamada

    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, 2019.07, Oral Presentation(general)

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

    European Human Genetics Conference, 2019.06, Oral Presentation(general)

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

    Yamada Mamiko

    第41回日本小児遺伝学会学術集会, 2019.01, Oral Presentation(general)

display all >>

Research Projects of Competitive Funds, etc. 【 Display / hide

  • 末梢血トランスクリプトームの外れ値解析:エクソーム解析の限界を超えるアプローチ

    2021.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 山田 茉未子, Grant-in-Aid for Early-Career Scientists , Principal Investigator

  • 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―

    2020.09
    -
    2021.03

    Research grant, Principal Investigator

  • 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

    2020.04
    -
    2021.09

    Research grant, Principal Investigator

  • 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

    2020.04
    -
    2021.03

    Research grant, Principal Investigator

  • 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

    2019.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 山田 茉未子, Grant-in-Aid for Early-Career Scientists , Principal Investigator

display all >>

Awards 【 Display / hide

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

    2020.01

    Type of Award: Awards of International Conference, Council and Symposium

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

    2019.07,  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

    Type of Award: Awards of International Conference, Council and Symposium

  • 優秀演題賞、日本小児遺伝学会

    2019.01, 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

    Type of Award: Awards of National Conference, Council and Symposium

 

Memberships in Academic Societies 【 Display / hide

  • 日本小児内分泌学会, 

    2015
    -
    Present
  • 日本小児科学会, 

    2013.04
    -
    Present
  • The Japan Society of Human Genetics

     
  • The Japanese teratology society

     
  • The Japanese association of school health

     

display all >>