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

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 <i>SIDT2</i> 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.

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Publication Details

Journal
Journal of Medical Genetics
Published
2025-06-20
DOI
https://doi.org/10.1136/jmg-2025-110654
Citations
1
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
0.81

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article

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

Jeiwook Chae, Martine Tétreault, Ken C. Pang, Sean Massey et al.
1 citations
Journal of Medical Genetics
RNA regulation and disease
0.81
article

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

Jeiwook Chae, Martine Tétreault, Ken C. Pang, Sean Massey, Craig P. Hunter, Tan A. Nguyen, Blake R. C. Smith, John Christodoulou, Simranpreet Kaur, Grace Yoon
article en
1 citations

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 <i>SIDT2</i> 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.

Journal of Medical GeneticsVol. 62(9)
The University of Sydney (AU), Royal Children's Hospital (AU), Harvard University (US), The University of Melbourne (AU), University of California, San Francisco (US), Walter and Eliza Hall Institute of Medical Research (AU), Hospital for Sick Children (CA), Centre Hospitalier de l’Université de Montréal (CA), Murdoch Children's Research Institute (AU)
Genome Canada, Children's Hospital of Eastern Ontario Foundation, Ontario Genomics Institute, Royal Australasian College of Physicians, State Government of Victoria, Hospital for Sick Children, Lung Foundation Australia, Canadian Institutes of Health Research, National Health and Medical Research Council, Cancer Council Victoria
Good health and well-being
Openalex Percentile: Top 27%
RNA regulation and disease
0.81
DOISourceOpenAlex
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