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@ARTICLE{Loureiro:286090,
author = {Loureiro, Joana R and Castro, Ana F and Figueiredo, Ana S
and Eufrásio, Ana and Dhingra, Ashutosh and Galhardo,
Mafalda and Marcelino, Hugo and Rodrigues, Catarina C and
Sampaio, Paula and Azevedo, Maria and Sousa, Mafalda and
Dória, Sofia and Rizzu, Patrizia and Heutink, Peter and
Bessa, José and Silveira, Isabel},
title = {{T}he insertion of an {ATTTC} repeat in an {A}lu element
hyperactivates a neurodevelopmental enhancer in
spinocerebellar ataxia type 37.},
journal = {Cell reports},
volume = {45},
number = {4},
issn = {2211-1247},
address = {Maryland Heights, MO},
publisher = {Cell Press},
reportid = {DZNE-2026-00386},
pages = {117146},
year = {2026},
abstract = {Alu elements are evolutionarily very old primate-specific
interspersed repeat elements that constitute $∼11\%$ of
the human genome. They are a source of short tandem repeats
(STRs), which often expand in size and cause inherited
neuromuscular and neurodegenerative disorders. How expanded
STR insertion mutations within Alu STRs culminate in disease
remains unknown. Here, we report an Alu STR located in an
intron of DAB1 that functions as a neurodevelopmental
enhancer. We demonstrate that an ATTTC repeat insertion in
this DAB1 Alu STR, known to cause spinocerebellar ataxia
type 37 (SCA37), hyperactivates a neurodevelopmental DAB1
enhancer. Importantly, we show that neurons derived from
SCA37 subjects have higher levels of DAB1 expression and
that DAB1 overexpression causes abnormal axonal pathfinding
in vivo. Overall, these results establish that neuronal
dysregulation of a developmental DAB1 Alu STR enhancer
contributes to SCA37 pathogenesis, an unexplored mechanism
likely acting in many Alu STR diseases, potentially
reshaping the therapeutic landscape.},
keywords = {4C-seq (Other) / CAGE (Other) / CP: genomics (Other) / CP:
neuroscience (Other) / DAB1 primate-specific Alu element
(Other) / SCA37 (Other) / STR (Other) / axonal pathfinding
(Other) / cap analysis of gene expression (Other) /
cerebellar transcriptional enhancer (Other) / circularized
chromosome conformation capture sequencing (Other) / iPSN
(Other) / neurodegenerative disease (Other) /
pentanucleotide repeat expansion (Other) / short tandem
repeat (Other) / spinocerebellar ataxia type 37 (Other)},
cin = {AG Heutink / AG Rizzu},
ddc = {610},
cid = {I:(DE-2719)1210002 / I:(DE-2719)1210009},
pnm = {354 - Disease Prevention and Healthy Aging (POF4-354)},
pid = {G:(DE-HGF)POF4-354},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41871099},
doi = {10.1016/j.celrep.2026.117146},
url = {https://pub.dzne.de/record/286090},
}