Novel genotype-phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
Sanchez-Flores, Marina (Institut Germans Trias i Pujol)
Corral-Juan, Marc (Institut Germans Trias i Pujol)
Gasch-Navalón, Esther (Institut Germans Trias i Pujol)
Cirillo, Davide (Barcelona Supercomputing Center (Barcelona, Catalunya))
Sanchez, Ivelisse (Institut Germans Trias i Pujol)
Matilla-Dueñas, Antoni (Institut Germans Trias i Pujol)

Date:	2024
Abstract:	Spinocerebellar ataxia subtype 37 (SCA37) is a rare disease originally identified in ataxia patients from the Iberian Peninsula with a pure cerebellar syndrome. SCA37 patients carry a pathogenic intronic (ATTTC)n repeat insertion flanked by two polymorphic (ATTTT)n repeats in the Disabled-1 (DAB1) gene leading to cerebellar dysregulation. Herein, we determine the precise configuration of the pathogenic 5ʹ(ATTTT)n-(ATTTC)n-3ʹ(ATTTT)n SCA37 alleles by CRISPR-Cas9 and long-read nanopore sequencing, reveal their epigenomic signatures in SCA37 lymphocytes, fibroblasts, and cerebellar samples, and establish new molecular and clinical correlations. The 5ʹ(ATTTT)n-(ATTTC)n-3ʹ(ATTTT)n pathogenic allele configurations revealed repeat instability and differential methylation signatures. Disease age of onset negatively correlated with the (ATTTC)n, and positively correlated with the 3ʹ(ATTTT)n. Geographic origin and gender significantly correlated with age of onset. Furthermore, significant predictive regression models were obtained by machine learning for age of onset and disease evolution by considering gender, the (ATTTC)n, the 3ʹ(ATTTT)n, and seven CpG positions differentially methylated in SCA37 cerebellum. A common 964-kb genomic region spanning the (ATTTC)n insertion was identified in all SCA37 patients analysed from Portugal and Spain, evidencing a common origin of the SCA37 mutation in the Iberian Peninsula originating 859 years ago (95% CI 647-1378). In conclusion, we demonstrate an accurate determination of the size and configuration of the regulatory 5ʹ(ATTTT)n-(ATTTC)n-3ʹ(ATTTT)n repeat tract, avoiding PCR bias amplification using CRISPR/Cas9-enrichment and nanopore long-read sequencing, resulting relevant for accurate genetic diagnosis of SCA37. Moreover, we determine novel significant genotype-phenotype correlations in SCA37 and identify differential cerebellar allele-specific methylation signatures that may underlie DAB1 pathogenic dysregulation.
Grants:	Instituto de Salud Carlos III PI17/00534 Ministerio de Economía y Competitividad PT13/0010/0009
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Adult ; Age of Onset ; Aged ; Alleles ; Cerebellum ; DNA Methylation ; Female ; Genetic Association Studies ; Humans ; Male ; Middle Aged ; Mutagenesis, Insertional ; Spinocerebellar Ataxias
Published in:	Human Genetics, Vol. 143 Núm. 3 (march 2024) , p. 211-232, ISSN 1432-1203

DOI: 10.1007/s00439-024-02644-7
PMID: 38396267

22 p, 5.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles