Hexanucleotide repeat expansion in SCA36 reduces the expression of genes involved in ribosome biosynthesis and protein translation

• Published in: Journal of human genetics Vol. 69; no. 9; pp. 411 - 416
• Main Authors: Morikawa, Takuya, Miura, Shiroh, Uchiyama, Yusuke, Hiruki, Shigeyoshi, Sun, Yinrui, Fujioka, Ryuta, Shibata, Hiroki
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2024
• Subjects: Adult; Age; Ataxia; Atrophy; Biosynthesis; Cerebellar ataxia; Cerebellum; DNA Repeat Expansion - genetics; Dysarthria; Female; Gait; Gene Expression Regulation; Genes; Genomics; Hearing loss; Hereditary diseases; Humans; Hypertension; Male; Middle Aged; NOP56 gene; Nuclear Proteins - genetics; Ontology; Pathogenesis; Patients; Pedigree; Peripheral blood; Protein biosynthesis; Protein Biosynthesis - genetics; Ribonucleic acid; Ribosomes - genetics; Ribosomes - metabolism; RNA; rRNA; Southern blotting; Spinocerebellar Ataxias - genetics; Translation
• ISSN: 1434-5161; 1435-232X; 1435-232X
• DOI: 10.1038/s10038-024-01260-7

Hereditary spinocerebellar ataxia (SCA) is a group of clinically and genetically heterogeneous inherited disorders characterized by slowly progressive cerebellar ataxia. We ascertained a Japanese pedigree with autosomal dominant SCA comprising four family members, including two patients. We identified a GGCCTG repeat expansion of intron 1 in the NOP56 gene by Southern blotting, resulting in a molecular diagnosis of SCA36. RNA sequencing using peripheral blood revealed that the expression of genes involved in ribosomal organization and translation was decreased in patients carrying the GGCCTG repeat expansion. Genes involved in pathways associated with ribosomal organization and translation were enriched and differentially expressed in the patients. We propose a novel hypothesis that the GGCCTG repeat expansion contributes to the pathogenesis of SCA36 by causing a global disruption of translation resulting from ribosomal dysfunction.