SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.

Autor: Naruse H; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Ishiura H; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Esaki K; Department of Biotechnology and Life Sciences, Faculty of Biotechnology and Life Sciences, Sojo University, Kumamoto, Japan., Mitsui J; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Satake W; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Greimel P; Laboratory for Cell Function Dynamics, RIKEN Centre for Brain Sciences, Wako, Saitama, Japan., Shingai N; Division of Applied Life Science, Graduate School of Engineering, Sojo University, Kumamoto, Japan., Machino Y; Department of Neurology, National Hospital Organization Mie National Hospital, Tsu, Mie, Japan., Kokubo Y; Kii ALS/PDC Research Center, Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie, Japan., Hamaguchi H; Department of Neurology, Kita-Harima Medical Center, Ono, Hyogo, Japan., Oda T; Department of Neurology, Kita-Harima Medical Center, Ono, Hyogo, Japan., Ikkaku T; Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.; Department of Neurology, Hyogo Prefectural Rehabilitation Central Hospital, Kobe, Hyogo, Japan., Yokota I; Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.; Department of Neurology, National Hospital Organization Hyogo-Chuo National Hospital, Sanda, Hyogo, Japan., Takahashi Y; Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan., Suzuki Y; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan., Matsukawa T; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Goto J; Department of Neurology, International University of Health and Welfare Ichikawa Hospital, Chiba, Japan., Koh K; Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.; Department of Neurology, Yumura Onsen Hospital, Yamanashi, Japan., Takiyama Y; Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.; Department of Neurology, Fuefuki Central Hospital, Yamanashi, Japan., Morishita S; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan., Yoshikawa T; Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan., Tsuji S; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan., Toda T; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Jazyk: angličtina
Zdroj: Annals of clinical and translational neurology [Ann Clin Transl Neurol] 2024 Apr; Vol. 11 (4), pp. 946-957. Date of Electronic Publication: 2024 Feb 05.
DOI: 10.1002/acn3.52013
Abstrakt: Objective: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies.
Methods: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants.
Results: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction.
Interpretation: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.
(© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
Databáze: MEDLINE
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