TY - JOUR
T1 - DNA instability in replicating Huntington's disease lymphoblasts
AU - Cannella, Milena
AU - Maglione, Vittorio
AU - Martino, Tiziana
AU - Ragona, Giuseppe
AU - Frati, Luigi
AU - Li, Guo Min
AU - Squitieri, Ferdinando
N1 - Funding Information:
We thank the European Huntington's Disease Network, all patients and their families (Associazione Italiana Corea di Huntington-Neuromed), the Italian Health Ministry and Siena Biotech (FS, COFIN 2006), for their kind cooperation and support. The financial support of Telethon – Italy to FS (Grant no. GGP06181), is gratefully acknowledged.
PY - 2009/2/11
Y1 - 2009/2/11
N2 - Background: The expanded CAG repeat in the Huntington's disease (HD) gene may display tissue-specific variability (e.g. triplet mosaicism) in repeat length, the longest mutations involving mitotic (germ and glial cells) and postmitotic (neurons) cells. What contributes to the triplet mutability underlying the development of HD nevertheless remains unknown. We investigated whether, besides the increased DNA instability documented in postmitotic neurons, possible environmental and genetic mechanisms, related to cell replication, may concur to determine CAG repeat mutability. To test this hypothesis we used, as a model, cultured HD patients' lymphoblasts with various CAG repeat lengths. Results: Although most lymphoblastoid cell lines (88%) showed little or no repeat instability even after six or more months culture, in lymphoblasts with large expansion repeats beyond 60 CAG repeats the mutation size and triplet mosaicism always increased during replication, implying that the repeat mutability for highly expanded mutations may quantitatively depend on the triplet expansion size. None of the investigated genetic factors, potentially acting in cis to the mutation, significantly influence the repeat changes. Finally, in our experiments certain drugs controlled triplet expansion in two prone-to-expand HD cell lines carrying large CAG mutations. Conclusion: Our data support quantitative evidence that the inherited CAG length of expanded alleles has a major influence on somatic repeat variation. The longest triplet expansions show wide somatic variations and may offer a mechanistic model to study triplet drug-controlled instability and genetic factors influencing it.
AB - Background: The expanded CAG repeat in the Huntington's disease (HD) gene may display tissue-specific variability (e.g. triplet mosaicism) in repeat length, the longest mutations involving mitotic (germ and glial cells) and postmitotic (neurons) cells. What contributes to the triplet mutability underlying the development of HD nevertheless remains unknown. We investigated whether, besides the increased DNA instability documented in postmitotic neurons, possible environmental and genetic mechanisms, related to cell replication, may concur to determine CAG repeat mutability. To test this hypothesis we used, as a model, cultured HD patients' lymphoblasts with various CAG repeat lengths. Results: Although most lymphoblastoid cell lines (88%) showed little or no repeat instability even after six or more months culture, in lymphoblasts with large expansion repeats beyond 60 CAG repeats the mutation size and triplet mosaicism always increased during replication, implying that the repeat mutability for highly expanded mutations may quantitatively depend on the triplet expansion size. None of the investigated genetic factors, potentially acting in cis to the mutation, significantly influence the repeat changes. Finally, in our experiments certain drugs controlled triplet expansion in two prone-to-expand HD cell lines carrying large CAG mutations. Conclusion: Our data support quantitative evidence that the inherited CAG length of expanded alleles has a major influence on somatic repeat variation. The longest triplet expansions show wide somatic variations and may offer a mechanistic model to study triplet drug-controlled instability and genetic factors influencing it.
UR - http://www.scopus.com/inward/record.url?scp=61549143317&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=61549143317&partnerID=8YFLogxK
U2 - 10.1186/1471-2350-10-11
DO - 10.1186/1471-2350-10-11
M3 - Article
C2 - 19210789
AN - SCOPUS:61549143317
SN - 1471-2350
VL - 10
JO - BMC Medical Genetics
JF - BMC Medical Genetics
M1 - 11
ER -