Biallelic SIDT2 loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of SIDT2 in mice

Nguyen, T; Yoon, G; Smith, BRC; T&#233;treault, M; Chae, J; Massey, S; Kaur, S; Christodoulou, J; Hunter, CP; Pang, KC

Author(s): Nguyen, T; Yoon, G; Smith, BRC; Tétreault, M; Chae, J; Massey, S; Kaur, S; Christodoulou, J; Hunter, CP; Pang, KC;
Details: Publication Year 2025-08-20,Volume 62,Issue #9,Page 592-599
Journal Title: Journal of Medical Genetics
Abstract: SIDT2 (Systemic Interference Deficient 1 Transmembrane Family Member 2) is a lysosomal membrane protein involved in RNA degradation via RNAutophagy. While animal models have indicated a link between SIDT2 deficiency and lysosomal storage disorders, no human cases have been reported. Here, we report a child with biallelic SIDT2 missense variants (p.Arg529Trp, p.Arg678Trp), who developed progressive neurological decline with cerebellar atrophy and Parkinsonian features. Functional studies revealed that the affected individual's variants disrupted the ability of SIDT2 to interact with RNA. Fibroblasts from the affected individual showed impaired autophagy, characterised by abnormal accumulation of autophagy markers. In mouse models, Sidt2 was found to be highly expressed in the brain, particularly in the hippocampus and cerebellum. Sidt2 loss-of-function in mice resulted in not only impaired autophagy in the brain but also neurological dysfunction, including motor incoordination and eventual seizures. These findings suggest that SIDT2 deficiency contributes to both autophagic dysfunction and neurodegenerative processes, providing insight into a potential role in human neurological disease.
Publisher: BMJ
Keywords: Animals; Child; Humans; Mice; Alleles; Autophagy/genetics; Brain/pathology/metabolism; *Cerebellar Ataxia/genetics/pathology; Cerebellum/pathology; Disease Models, Animal; *Loss of Function Mutation/genetics; *Lysosomal Storage Diseases/genetics/pathology; Lysosomes/pathology/genetics/metabolism; Mutation, Missense; Genetic Diseases, Inborn; Neurodegenerative Diseases
Research Division(s): Genetics and Gene Regulation
PubMed ID: 40541391
Publisher's Version: https://doi.org/10.1136/jmg-2025-110654
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-29 08:41:20

Last Modified: 2025-08-29 08:41:29