title: Somatic expansion in mouse and human carriers of fragile X premutation alleles.
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.
authors.affiliation: Section on Gene Structure and Disease, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892–0830, USA.
authors.forename: Rachel Adihe
authors.initials: RA
authors.lastname: Lokanga
authors.forename: Ali
authors.initials: A
authors.lastname: Entezam
authors.forename: Daman
authors.initials: D
authors.lastname: Kumari
authors.forename: Dmitry
authors.initials: D
authors.lastname: Yudkin
authors.forename: Mei
authors.initials: M
authors.lastname: Qin
authors.forename: Carolyn Beebe
authors.initials: CB
authors.lastname: Smith
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006579:Heterozygote; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D000074081:MutS Homolog 3 Protein; D011506:Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D011506:Proteins; C089762:Msh3 protein, mouse; C102997:Msh6 protein, mouse; C497173:Msh2 protein, mouse