doi: 10.15252/emmm.202114095.


Online ahead of print.

Barbara A Perez 
1
 
2
Hannah K Shorrock 
1
 
2
Monica Banez-Coronel 
1
 
2
Tao Zu 
1
 
2
Lisa El Romano 
1
 
2
Lauren A Laboissonniere 
1
 
2
Tammy Reid 
1
 
2
Yoshio Ikeda 
3
Kaalak Reddy 
4
Christopher M Gomez 
5
Thomas Bird 
6
 
7
Tetsuo Ashizawa 
8
Lawrence J Schut 
9
Alfredo Brusco 
10
 
11
J Andrew Berglund 
1
 
4
Lis F Hasholt 
12
Jorgen E Nielsen 
13
S H Subramony 
1
 
14
Laura Pw Ranum 
1
 
2
 
14
 
15

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Barbara A Perez et al.


EMBO Mol Med.


.

Free article

Abstract

Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p-eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.


Keywords:

RAN translation; cis-modifier; reduced penetrance; sequence interruptions; spinocerebellar ataxia type 8.

References

    1. Ayhan F, Perez BA, Shorrock HK, Zu T, Banez-Coronel M, Reid T, Furuya H, Clark HB, Troncoso JC, Ross CA et al (2018) SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. EMBO J 37: e99023

    1. Bañez-Coronel M, Ayhan F, Tarabochia A, Zu T, Perez B, Tusi S, Pletnikova O, Borchelt D, Ross C, Margolis R et al (2015) RAN translation in huntington disease. Neuron 88: 667-677

    1. Banez-Coronel M, Ranum LPW (2019) Repeat-associated non-AUG (RAN) translation: insights from pathology. Lab Invest 99: 929-942

    1. Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, Guharoy M, De Decker M, Jaspers T, Ryan VH et al (2017) Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol Cell 65: 1044-1055.e1045

    1. Braida C, Stefanatos RKA, Adam B, Mahajan N, Smeets HJM, Niel F, Goizet C, Arveiler B, Koenig M, Lagier-Tourenne C et al (2010) Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients. Hum Mol Genet 19: 1399-1412



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