Premium
Somatic Expansion in Mouse and Human Carriers of Fragile X Premutation Alleles
Author(s) -
Lokanga Rachel Adihe,
Entezam Ali,
Kumari Daman,
Yudkin Dmitry,
Qin Mei,
Smith Carolyn Beebe,
Usdin Karen
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22177
Subject(s) - biology , somatic cell , trinucleotide repeat expansion , germline , allele , fragile x syndrome , penetrance , genetics , germline mosaicism , untranslated region , fmr1 , germline mutation , gene , mutation , phenotype , messenger rna
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.