Dataset Information

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

ABSTRACT: Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.

SUBMITTER: Cunha P

PROVIDER: S-EPMC10357418 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Cunha Paulina P Petit Emilien E Coutelier Marie M Coarelli Giulia G Mariotti Caterina C Faber Jennifer J Van Gaalen Judith J Damasio Joana J Fleszar Zofia Z Tosi Michele M Rocca Clarissa C De Michele Giovanna G Minnerop Martina M Ewenczyk Claire C Santorelli Filippo M FM Heinzmann Anna A Bird Thomas T Amprosi Matthias M Indelicato Elisabetta E Benussi Alberto A Charles Perrine P Stendel Claudia C Romano Silvia S Scarlato Marina M Le Ber Isabelle I Bassi Maria Teresa MT Serrano Mercedes M Schmitz-Hübsch Tanja T Doss Sarah S Van Velzen Gijs A J GAJ Thomas Quentin Q Trabacca Antonio A Ortigoza-Escobar Juan Dario JD D'Arrigo Stefano S Timmann Dagmar D Pantaleoni Chiara C Martinuzzi Andrea A Besse-Pinot Elsa E Marsili Luca L Cioffi Ettore E Nicita Francesco F Giorgetti Alejandro A Moroni Isabella I Romaniello Romina R Casali Carlo C Ponger Penina P Casari Giorgio G De Bot Susanne T ST Ristori Giovanni G Blumkin Lubov L Borroni Barbara B Goizet Cyril C Marelli Cecilia C Boesch Sylvia S Anheim Mathieu M Filla Alessandro A Houlden Henry H Bertini Enrico E Klopstock Thomas T Synofzik Matthis M Riant Florence F Zanni Ginevra G Magri Stefania S Di Bella Daniela D Nanetti Lorenzo L Sequeiros Jorge J Oliveira Jorge J Van de Warrenburg Bart B Schöls Ludger L Taroni Franco F Brice Alexis A Durr Alexandra A

American journal of human genetics 20230609 7

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucl ...[more]

PMID: 37301203

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Project description:The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders.

Dataset Information

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Publications

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Similar Datasets

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