Somatic Expansion in Mouse and Human Carriers of Fragile X Premutation Alleles

Authors

  • Rachel Adihe Lokanga,

    1. Section on Gene Structure and Disease, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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  • Ali Entezam,

    1. Section on Gene Structure and Disease, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
    2. GeneDx, Gaithersburg, Maryland
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  • Daman Kumari,

    1. Section on Gene Structure and Disease, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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  • Dmitry Yudkin,

    1. Section on Gene Structure and Disease, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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  • Mei Qin,

    1. Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Carolyn Beebe Smith,

    1. Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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  • Karen Usdin

    Corresponding author
    • Section on Gene Structure and Disease, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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  • Communicated by Haig H. Kazazian, Jr.

  • Contract grant sponsors: Intramural program of the NIDDK, NIH (DK057808 to K.U.).

Correspondence to: Karen Usdin, Building 8, Room 2A19, National Institutes of Health, 8 CENTER DR MSC 0830, Bethesda, MD 20892–0830. E-mail: ku@helix.nih.gov

ABSTRACT

Repeat expansion diseases result from expansion of a specific tandem repeat. The three fragile X-related disorders (FXDs) arise from germline expansions of a CGG•CCG repeat tract in the 5′ UTR (untranslated region) of the fragile X mental retardation 1 (FMR1) gene. We show here that in addition to germline expansion, expansion also occurs in the somatic cells of both mice and humans carriers of premutation alleles. Expansion in mice primarily affects brain, testis, and liver with very little expansion in heart or blood. Our data would be consistent with a simple two-factor model for the organ specificity. Somatic expansion in humans may contribute to the mosaicism often seen in individuals with one of the FXDs. Because expansion risk and disease severity are related to repeat number, somatic expansion may exacerbate disease severity and contribute to the age-related increased risk of expansion seen on paternal transmission in humans. As little somatic expansion occurs in murine lymphocytes, our data also raise the possibility that there may be discordance in humans between repeat numbers measured in blood and that present in brain. This could explain, at least in part, the variable penetrance seen in some of these disorders.

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