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A splicing mutation of proteolipid protein 1 in Pelizaeus-Merzbacher disease

  • Taku Omata
    Affiliations
    Division of Child Neurology, Chiba Children’s Hospital, Chiba, Japan
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  • Jun-ichi Nagai
    Affiliations
    Laboratory Medicine, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama 232-855, Japan
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  • Hiroko Shimbo
    Affiliations
    Division of Neurology, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama 232-855, Japan
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  • Shiro Koizume
    Affiliations
    Division of Neurology, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama 232-855, Japan

    Division of Genetics, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama 232-855, Japan

    Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-0815, Japan
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  • Yohei Miyagi
    Affiliations
    Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-0815, Japan
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  • Kenji Kurosawa
    Affiliations
    Division of Genetics, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama 232-855, Japan
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  • Sumimasa Yamashita
    Affiliations
    Division of Neurology, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama 232-855, Japan
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  • Hitoshi Osaka
    Correspondence
    Corresponding author at: Department of Pediatrics, Jichi Medical School, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan. Tel.: +81 285 58 7366; fax: +81 285 44 6123.
    Affiliations
    Division of Neurology, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama 232-855, Japan

    Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-0815, Japan

    Department of Pediatrics, Jichi Medical School, Shimono, Japan
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  • Ken Inoue
    Affiliations
    Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
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Published:December 22, 2015DOI:https://doi.org/10.1016/j.braindev.2015.12.002

      Abstract

      A patient with an unusually mild form of Pelizaeus-Merzbacher disease was studied. Clinically, mild developmental delay with acquisition of assisted walking at 16 months and mild spastic tetraplegia were evident, but no nystagmus, cerebellar, or extra-pyramidal signs were present. PLP1 mutation analysis revealed a nucleotide substitution adjacent to the acceptor site of intron 3, NM_000533.4:c.454-9T>G. Expression analysis using the patient’s leukocytes demonstrated an additional abnormal transcript including the last 118 bp of intron 3. In silico prediction analysis suggested the reduction of wild-type acceptor activity, which presumably evokes the cryptic splicing variant. Putative cryptic transcript results in premature termination, which may explain the mild clinical phenotype observed in this patient.

      Keywords

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      References

        • Inoue K.
        PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2.
        Neurogenetics. 2005; 6: 1-16
        • Bonnet-Dupeyron M.N.
        • Combes P.
        • Santander P.
        • Cailloux F.
        • Boespflug-Tanguy O.
        • Vaurs-Barriere C.
        PLP1 splicing abnormalities identified in Pelizaeus-Merzbacher disease and SPG2 fibroblasts are associated with different types of mutations.
        Hum Mutat. 2008; 29: 1028-1036
        • Hobson G.M.
        • Davis A.P.
        • Stowell N.C.
        • Kolodny E.H.
        • Sistermans E.A.
        • de Coo I.F.
        • et al.
        Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease.
        Neurology. 2000; 55: 1089-1096
        • Osaka H.
        • Kawanishi C.
        • Inoue K.
        • Onishi H.
        • Kobayashi T.
        • Sugiyama N.
        • et al.
        Pelizaeus-Merzbacher disease: three novel mutations and implication for locus heterogeneity.
        Ann Neurol. 1999; 45: 59-64
        • Reese M.G.
        • Eeckman F.H.
        • Kulp D.
        • Haussler D.
        Improved splice site detection in Genie.
        J Comput Biol. 1997; 4: 311-323
        • Desmet F.O.
        • Hamroun D.
        • Lalande M.
        • Collod-Beroud G.
        • Claustres M.
        • Beroud C.
        Human Splicing Finder: an online bioinformatics tool to predict splicing signals.
        Nucleic Acids Res. 2009; 37: e67
        • Yeo G.
        • Burge C.B.
        Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals.
        J Comput Biol. 2004; 11: 377-394
        • Wang M.
        • Marin A.
        Characterization and prediction of alternative splice sites.
        Gene. 2006; 366: 219-227
        • Cailloux F.
        • Gauthier-Barichard F.
        • Mimault C.
        • Isabelle V.
        • Courtois V.
        • Giraud G.
        • et al.
        Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations.
        Eur J Hum Genet. 2000; 8: 837-845
        • Stenson P.D.
        • Mort M.
        • Ball E.V.
        • Shaw K.
        • Phillips A.
        • Cooper D.N.
        The human gene mutation database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.
        Hum Genet. 2014; 133: 1-9