Communicated by Haig H. Kazazian, Jr.
Somatic Expansion in Mouse and Human Carriers of Fragile X Premutation Alleles
Article first published online: 4 OCT 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 1, pages 157–166, January 2013
How to Cite
Lokanga, R. A., Entezam, A., Kumari, D., Yudkin, D., Qin, M., Smith, C. B. and Usdin, K. (2013), Somatic Expansion in Mouse and Human Carriers of Fragile X Premutation Alleles. Hum. Mutat., 34: 157–166. doi: 10.1002/humu.22177
Contract grant sponsors: Intramural program of the NIDDK, NIH (DK057808 to K.U.).
- Issue published online: 20 DEC 2012
- Article first published online: 4 OCT 2012
- Accepted manuscript online: 8 AUG 2012 04:26PM EST
- Manuscript Accepted: 17 JUL 2012
- Manuscript Received: 24 APR 2012
- Intramural program of the NIDDK, NIH. Grant Number: DK057808
- fragile X-related disorders;
- somatic expansion;
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.