Sacsin levels in PBMCs: A diagnostic assay for SACS variants in peripheral blood cells - A PROSPAX study
MOVEMENT DISORDERS, vol.39, no.12, pp.2291-2297, 2024 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 39 Issue: 12
- Publication Date: 2024
- Doi Number: 10.1002/mds.30012
- Journal Name: MOVEMENT DISORDERS
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Page Numbers: pp.2291-2297
- Acibadem Mehmet Ali Aydinlar University Affiliated: Yes
Abstract
Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a common recessive ataxia that is still underdiagnosed worldwide. An easily accessible diagnostic biomarker might help to diagnostically confirm patients presenting SACS variants of unknown significance (VUS)or atypical phenotypes.
Objectives: To detect sacsin in peripheral blood mono-nuclear cells (PBMCs) and to validate its diagnostic bio-marker quality to discriminate biallelic SACS patients (including patients with VUS and/or atypical phenotypes)against healthy controls, non-ARSACS spastic ataxia patients, and heterozygous SACS carriers.
Methods: Sacsin protein levels in PBMCs were assessed in patients versus controls and validated in skin-derived fibroblasts.
Results: Patients with biallelic SACS variants-including patients with VUS and/or atypical phenotypes-showed loss of sacsin in PBMCs, with discriminative performance against healthy, heterozygous, and non-ARSACS controls. This included all investigated SACS missense variants. Also, C-terminal variants escaping nonsense-mediated decay, while not differing from controls in expression level, showed lower molecular weight in this assay.
Conclusions: Assessing sacsin levels using PBMCs offers an easy, peripherally accessible diagnostic bio-marker for ARSACS, with PBMCs being much less invasive and easier to handle than fibroblasts. Additionally, this might be a potential target-engagement blood biomarker for sacsin-increasing therapies.