Timing of Expansion of Fragile X Premutation Alleles During Intergenerational Transmission in a Mouse Model of the Fragile X-Related Disorders

Frontiers in Genetics
Xiaonan Zhao, Karen Usdin

Abstract

Fragile X syndrome (FXS) is caused by the maternal expansion of an unstable CGG-repeat tract located in the first exon of the FMR1 gene. Further changes in repeat number occur during embryogenesis resulting in individuals sometimes being highly mosaic. Here we show in a mouse model that, in males, expansions are already present in primary spermatocytes with no additional expansions occurring in later stages of gametogenesis. We also show that, in females, expansion occurs in the post-natal oocyte. Additional expansions and a high frequency of large contractions are seen in two-cell stage embryos. Expansion in oocytes, which are non-dividing, would be consistent with a mechanism involving aberrant DNA repair or recombination rather than a problem with chromosomal replication. Given the difficulty of replicating large CGG-repeat tracts, we speculate that very large expanded alleles may be prone to contract in the mitotically proliferating spermatagonial stem cells in men. However, expanded alleles may not be under such pressure in the non-dividing oocyte. The high degree of both expansions and contractions seen in early embryos may contribute to the high frequency of somatic mosaicism that is observed in humans. Our data thus sug...Continue Reading

References

Jul 15, 1994·American Journal of Medical Genetics·S L NolinC S Dobkin
Nov 14, 1997·Nature Genetics·G M SamadashwilyS M Mirkin
Mar 30, 2001·Nature Genetics·I V Kovtun, C T McMurray
Sep 28, 2001·Journal of the Neurological Sciences·H HashidaI Kanazawa
Jan 30, 2003·Human Molecular Genetics·Vanessa C WheelerMarcy E MacDonald
Jul 15, 2003·Proceedings of the National Academy of Sciences of the United States of America·Song-Ro YoonNorman Arnheim
Sep 1, 1961·Experimental Cell Research·K BORUM
Jan 1, 2004·Molecular and Cellular Biology·Cédric SavouretGeneviève Gourdon
Mar 22, 2005·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Henri BastosPierre Fouchet
Feb 27, 2008·Proceedings of the National Academy of Sciences of the United States of America·Roman GonitelGillian P Bates
Jan 13, 2009·Nature Structural & Molecular Biology·Irina VoineaguSergei M Mirkin
Jan 31, 2009·Nature Protocols·Kaomei GuanGerd Hasenfuss
Oct 31, 2009·PLoS Genetics·Scott DitchEd Grabczyk
Dec 21, 2010·PLoS Genetics·Linda MøllersenArne Klungland
Feb 15, 2011·DNA Repair·Elisia D TichyPeter J Stambrook
Aug 14, 2012·Human Mutation·Rachel Adihe LokangaKaren Usdin
Dec 3, 2013·Molecular Cell·Jeannine GerhardtCarl L Schildkraut
Jan 15, 2014·Human Molecular Genetics·Dmitry YudkinKaren Usdin
Aug 12, 2014·Journal of Neurodevelopmental Disorders·Carolyn M YrigollenFlora Tassone
Sep 3, 2014·The Journal of Cell Biology·Jeannine GerhardtCarl L Schildkraut
Sep 12, 2014·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Sarah L NolinAndrew G Hadd
Dec 30, 2014·Endocrine Reviews·Katja HummitzschRaymond J Rodgers
Apr 30, 2015·American Journal of Medical Genetics. Part a·Kirin BasutaFlora Tassone

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Citations

Feb 16, 2020·The Journal of Biological Chemistry·Alexandra N Khristich, Sergei M Mirkin
May 3, 2019·American Journal of Medical Genetics. Part a·Sarah L NolinAndrew G Hadd
May 18, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Rula Zain, C I Edvard Smith
Jan 29, 2021·The Journal of Biological Chemistry·Alexandra N Khristich, Sergei M Mirkin
Aug 21, 2021·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Qiwei GuoTsang-Ming Ko

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Methods Mentioned

BETA
electrophoresis
PCR
genotyping
enzymatic dissociation
flow cytometry
FACS
fluorescence microscopy

Software Mentioned

GraphPad QuickCalcs
R script

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