Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb;25(2):100327.
doi: 10.1016/j.gim.2022.10.009. Epub 2022 Nov 23.

Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

Mathieu Barbier  1 , Claire-Sophie Davoine  1 , Emilien Petit  1 , Maximilien Porché  2 , Léna Guillot-Noel  1 , Sabrina Sayah  1 , Anne-Laure Fauret  3 , Jean-Philippe Neau  4 , Lucie Guyant-Maréchal  5 , Didier Deffond  6 , Christine Tranchant  7 , Cyril Goizet  8 , Giulia Coarelli  1 , Anna Castrioto  9 , Stephan Klebe  10 , Claire Ewenczyk  1 , Anna Heinzmann  1 , Perrine Charles  1 , Maya Tchikviladzé  1 , Christine Van Broeckhoven  11 , Alexis Brice  1 , Alexandra Durr  12
Affiliations
Free article

Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

Mathieu Barbier et al. Genet Med. 2023 Feb.
Free article

Abstract

Purpose: CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease.

Methods: We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47).

Results: STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode.

Conclusion: We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.

Keywords: SCA17; SCA48; STUB1, Spinocerebellar ataxia; TBP.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

Similar articles

See all similar articles

Cited by

  • Two more families supporting the existence of monogenic spinocerebellar ataxia 48.
    Palombo F, Vaisfeld A, Tropeano VC, Ormanbekova D, Bacchi I, Fiorini C, Peruzzi A, Morandi L, Liguori R, Carelli V, Rizzo G. Palombo F, et al. Neurogenetics. 2024 Jul;25(3):277-280. doi: 10.1007/s10048-024-00758-8. Epub 2024 Apr 16. Neurogenetics. 2024. PMID: 38625442
  • Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
    Cunha P, Petit E, Coutelier M, Coarelli G, Mariotti C, Faber J, Van Gaalen J, Damasio J, Fleszar Z, Tosi M, Rocca C, De Michele G, Minnerop M, Ewenczyk C, Santorelli FM, Heinzmann A, Bird T, Amprosi M, Indelicato E, Benussi A, Charles P, Stendel C, Romano S, Scarlato M, Le Ber I, Bassi MT, Serrano M, Schmitz-Hübsch T, Doss S, Van Velzen GAJ, Thomas Q, Trabacca A, Ortigoza-Escobar JD, D'Arrigo S, Timmann D, Pantaleoni C, Martinuzzi A, Besse-Pinot E, Marsili L, Cioffi E, Nicita F, Giorgetti A, Moroni I, Romaniello R, Casali C, Ponger P, Casari G, De Bot ST, Ristori G, Blumkin L, Borroni B, Goizet C, Marelli C, Boesch S, Anheim M, Filla A, Houlden H, Bertini E, Klopstock T, Synofzik M, Riant F, Zanni G, Magri S, Di Bella D, Nanetti L, Sequeiros J, Oliveira J, Van de Warrenburg B, Schöls L, Taroni F, Brice A, Durr A. Cunha P, et al. Am J Hum Genet. 2023 Jul 6;110(7):1098-1109. doi: 10.1016/j.ajhg.2023.05.009. Epub 2023 Jun 9. Am J Hum Genet. 2023. PMID: 37301203 Free PMC article.
  • The New Face of Dynamic Mutation-The CAA [CAG]n CAA CAG Motif as a Mutable Unit in the TBP Gene Causative for Spino-Cerebellar Ataxia Type 17.
    Hoffman-Zacharska D, Sulek A. Hoffman-Zacharska D, et al. Int J Mol Sci. 2024 Jul 26;25(15):8190. doi: 10.3390/ijms25158190. Int J Mol Sci. 2024. PMID: 39125760 Free PMC article.
  • Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.
    Méreaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, Monin ML, Anheim M, Le Ber I, Thobois S, Gobert F, Guillot-Noël L, Forlani S, Jornea L, Heinzmann A, Sangare A, Gaymard B, Guyant-Maréchal L, Charles P, Marelli C, Honnorat J, Degos B, Tison F, Sangla S, Simonetta-Moreau M, Salachas F, Tchikviladzé M, Castelnovo G, Mochel F, Klebe S, Castrioto A, Fenu S, Méneret A, Bourdain F, Wandzel M, Roth V, Bonnet C, Riant F, Stevanin G, Noël S, Fauret-Amsellem AL, Bahlo M, Lockhart PJ, Brais B, Renaud M, Brice A, Durr A. Méreaux JL, et al. EBioMedicine. 2024 Jan;99:104931. doi: 10.1016/j.ebiom.2023.104931. Epub 2023 Dec 27. EBioMedicine. 2024. PMID: 38150853 Free PMC article.
  • Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia.
    Gorcenco S, Kafantari E, Wallenius J, Karremo C, Alinder E, Dobloug S, Landqvist Waldö M, Englund E, Ehrencrona H, Wictorin K, Karrman K, Puschmann A. Gorcenco S, et al. J Neurol. 2024 Jan;271(1):526-542. doi: 10.1007/s00415-023-11990-x. Epub 2023 Oct 3. J Neurol. 2024. PMID: 37787810 Free PMC article.
See all "Cited by" articles

Publication types

Substances

Supplementary concepts

LinkOut - more resources