SPTLC1 p.Leu38Arg,a novel mutation associated with childhood ALS |
| |
| Institution: | 1. Institute for Clinical Chemistry, University Hospital and University of Zürich, Zürich, Switzerland;2. Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China;3. Institute for Biochemistry, University of Zürich; Zürich, Switzerland;4. National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China;1. Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People''s Hospital (Affiliated People''s Hospital, Hangzhou Medical College), Hangzhou, China;2. Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People''s Hospital (Affiliated People''s Hospital, Hangzhou Medical College), Hangzhou, China;3. International Medical Department, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China;4. Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China;1. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America;2. Department of Chemistry, Vanderbilt University, Nashville, TN 37235, United States of America;3. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America;1. Pharmaceutics, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino-machi, Nobeoka, Miyazaki 882-8508, Japan;2. Faculty of Pharmacy, Yasuda Women''s University, Hiroshima, Japan;3. Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan;4. Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan;1. Department of Medical Biotechnology and Translational Medicine, University of Milano, 20054 Segrate, Milano, Italy;2. UK Dementia Research Institute at UCL, London, UK;3. Neuro-Sys, 410 Chemin Départemental 60, 13120 Gardanne, France;4. Department of Immunology, St. Jude Children''s Research Hospital, Memphis, TN 38105, USA;5. Department of Chemistry, University of Milano, Milan, Italy;1. Department of Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA 23298, United States of America;2. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, United States of America;3. Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, United States of America;4. Richmond Department of Veterans Affairs Medical Center, Richmond, VA 23249, United States of America |
| |
| Abstract: | Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease. Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS. SPTLC1 encodes for a subunit of the serine-palmitoyltransferase (SPT) - the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL). SPT activity, and thus SL de novo synthesis, is tightly controlled by a homeostatic feedback mechanism mediated by ORMDL proteins. Here we report a novel SPTLC1p.L38R mutation in a young Chinese girl with a signature of juvenile ALS. The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs. All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT. Pertinent to the altered homeostatic control, lipid analysis showed overall increased SL levels in the patient plasma. An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells. Particularily dihydro-sphingolipids (dhSL) were signficantly increased in patient plasma and p.L38R mutant expressing cells. Increased dhSL formation has been previously linked to neurotoxicity and may be involved in the pathomechanism of SPTLC1-ALS mutations. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
