Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 9 (3)

Repeat Instability in the Fragile X-Related Disorders: Lessons From a Mouse Model

Affiliations

Repeat Instability in the Fragile X-Related Disorders: Lessons From a Mouse Model

Xiaonan Zhao et al. Brain Sci.

Abstract

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.

Keywords: CGG Repeat Expansion Disease; DNA instability; Non-homologous end-joining (NHEJ); base excision repair (BER); contraction; double-strand break repair (DSBR); expansion; mismatch repair (MMR); mosaicism; transcription coupled repair (TCR).

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript and in the decision to publish the results.

Figures

Figure 1
Figure 1
Different mouse organs show different propensities to expand. Repeat PCR was carried out on DNA extracted from different organs of a male mouse with 191 inherited repeats and analyzed as previously described [26]. The tail DNA sample was taken at 3 weeks, the remaining samples at 8 months of age. The arrowhead and dotted lines indicate the repeat number in the original inherited allele as assessed from tail DNA taken at 3 weeks of age. The numbers within each panel indicate the number of repeats added.
Figure 2
Figure 2
Change in the PM repeat PCR profiles and σ with age and extent of expansion. The PCR profiles and σs were generated from male mice as previously described [26,27]. (a) Liver PCR profiles of mice of different ages, all with an original allele of ~145 repeats. The arrowhead on the bottom of each panel and the dotted lines indicate the original inherited allele as assessed from tail DNA taken at 3 weeks of age. The numbers above the panels indicate the number of repeats added to the expanded allele. The σ of the stable allele and the expanded allele are shown in black and red, respectively. The examples shown in this panel are derived from previously published work [27]; (b) PCR profiles and corresponding σ for alleles in hearts and brains of 1-year old (155 repeats) and 6-month old (175 and 185 repeats) mice. The number associated with each arrowhead represents the number of repeats in the indicated allele. For the hearts, this number corresponds to the original inherited allele. For the brains, the repeat size reflects a gain of 6–9 repeats from the original allele.
Figure 3
Figure 3
Blood repeat PCR profiles for 3 human male PM carriers. Repeat PCR analysis was carried out as described previously [31]. The number associated with each arrowhead represents the number of repeats in the indicated allele. (a) Profiles of two individuals showing a unimodal profile with a sharp peak (top) and a broad peak (bottom); (b) Profiles generated from the same individual using samples taken 4 years apart. The dotted line in these panels indicates the size of the major allele at the earlier timepoint. A shift corresponding to the gain of 5 CGG repeats is seen in the later sample. In each case the σ values are for the major allele peak.
Figure 4
Figure 4
PM Repeat PCR profiles from the blood of human female PM carriers. The arrow in each instance indicates the stable allele with the indicated number of repeats. (a) Profiles for a female PM carrier without (top panel) and with (bottom panel) HpaII pre-digestion were generated as previously described [16]. The alleles on both the active and inactive X are shown in blue in the top panel and the alleles on the inactive X in green in the bottom panel; (b) Examples of very different bimodal PCR profiles; (c) Profiles for 2 women with different activation ratios (ARs); (d) Profiles of two females of similar ages and ARs, both with no AGG interruptions showing very different levels of somatic expansion.
Figure 5
Figure 5
Distribution of the changes in the repeat number seen in the brain of a 1-year old mouse with an inherited allele of 162 repeats. The repeat number of individual alleles was determined by small pool PCR of single genome equivalents as described previously [30]. The data shown represent 119 individual PCR reactions. The inset panels show the bulk PCR profiles for the heart and brain of the same animal.

Similar articles

See all similar articles

Cited by 1 PubMed Central articles

References

    1. Lozano R., Rosero C.A., Hagerman R.J. Fragile X spectrum disorders. Intractable Rare Dis. Res. 2014;3:134–146. doi: 10.5582/irdr.2014.01022. - DOI - PMC - PubMed
    1. Tassone F., Hagerman R.J., Taylor A.K., Gane L.W., Godfrey T.E., Hagerman P.J. Elevated levels of FMR1 mRNA in carrier males: A new mechanism of involvement in the fragile-X syndrome. Am. J. Hum. Genet. 2000;66:6–15. doi: 10.1086/302720. - DOI - PMC - PubMed
    1. Yrigollen C.M., Martorell L., Durbin-Johnson B., Naudo M., Genoves J., Murgia A., Polli R., Zhou L., Barbouth D., Rupchock A., et al. AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission. J. Neurodev. Disord. 2014;6:24. doi: 10.1186/1866-1955-6-24. - DOI - PMC - PubMed
    1. Nolin S.L., Glicksman A., Ersalesi N., Dobkin C., Brown W.T., Cao R., Blatt E., Sah S., Latham G.J., Hadd A.G. Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers. Genet. Med. 2015;17:358–364. doi: 10.1038/gim.2014.106. - DOI - PubMed
    1. Nolin S.L., Glicksman A., Houck G.E., Jr., Brown W.T., Dobkin C.S. Mosaicism in fragile X affected males. Am. J. Med. Genet. 1994;51:509–512. doi: 10.1002/ajmg.1320510444. - DOI - PubMed
Feedback