{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T14:14:57Z","timestamp":1782656097758,"version":"3.54.5"},"reference-count":30,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,26]],"date-time":"2024-05-26T00:00:00Z","timestamp":1716681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Multidisciplinary Digital Publishing Institute (Switzerland)","award":["offer 100% discount is available before 30 March 2024 (*article & review only*)"],"award-info":[{"award-number":["offer 100% discount is available before 30 March 2024 (*article & review only*)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the SPTLC1 or SPTLC2 variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of de novo sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Aim: Identifying new SPTLC1 or SPTLC2 \u201cgain-of-function\u201d variants raises the question as to their pathogenicity. This work focused on characterizing six new SPTLC1 variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Methods: Variants from six patients with HSAN1 were studied. In silico, CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. Results: In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two SPTLC1 variants were newly described as pathogenic: SPTLC1 NM_006415.4:c.998A&gt;G and NM_006415.4:c.1015G&gt;A. Discussion: The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.<\/jats:p>","DOI":"10.3390\/genes15060692","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:14:07Z","timestamp":1716804847000},"page":"692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional and Molecular Characterization of New SPTLC1 Missense Variants in Patients with Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1)"],"prefix":"10.3390","volume":"15","author":[{"given":"Julie","family":"Rochat","sequence":"first","affiliation":[{"name":"Unit\u00e9 Pathologies M\u00e9taboliques, \u00c9rythrocytaires et D\u00e9pistage P\u00e9rinatal, Service de Biochimie et Biologie Mol\u00e9culaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5161-1237","authenticated-orcid":false,"given":"Andr\u00e9","family":"Blavier","sequence":"additional","affiliation":[{"name":"Biokerden, 76130 Mont Saint-Aignan, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9verine","family":"Ruet","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Pathologies M\u00e9taboliques, \u00c9rythrocytaires et D\u00e9pistage P\u00e9rinatal, Service de Biochimie et Biologie Mol\u00e9culaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Vasseur","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Pathologies M\u00e9taboliques, \u00c9rythrocytaires et D\u00e9pistage P\u00e9rinatal, Service de Biochimie et Biologie Mol\u00e9culaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Puma","sequence":"additional","affiliation":[{"name":"Service Syst\u00e8me Nerveux P\u00e9riph\u00e9rique et Muscle, Universit\u00e9 C\u00f4te d\u2019Azur, Centre Hospitalier Universitaire Nice, 06000 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9atrice","family":"Desnous","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies Neuromusculaires de l\u2019Enfant, H\u00f4pital Timone Enfants, Assistance Publique H\u00f4pitaux de Marseille 13915 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Chan","sequence":"additional","affiliation":[{"name":"Service de Neurologie et Unit\u00e9 Neuro-Vasculaire, Centre Hospitalier de Valence, 26953 Valence, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilien","family":"Delmont","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies Neuromusculaires et SLA, H\u00f4pital de la Timone, Assistance Publique H\u00f4pitaux de Marseille, 13915 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahram","family":"Attarian","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies Neuromusculaires et SLA, H\u00f4pital de la Timone, Assistance Publique H\u00f4pitaux de Marseille, 13915 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul","family":"Juntas Morales","sequence":"additional","affiliation":[{"name":"Centre de Reference des Maladies Neuromusculaires Atlantique Occitanie Cara\u00efbe, D\u00e9partement de Neurologie, Centre Hospitalier Universitaire Montpellier, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6867-8238","authenticated-orcid":false,"given":"Isabelle","family":"Quadrio","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Neurog\u00e9n\u00e9tique Mol\u00e9culaire, Service de Biochimie et Biologie Mol\u00e9culaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9o","family":"Vidoni","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Neurog\u00e9n\u00e9tique Mol\u00e9culaire, Service de Biochimie et Biologie Mol\u00e9culaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8657-1271","authenticated-orcid":false,"given":"Nathalie","family":"Bonello-Palot","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique M\u00e9dicale, H\u00f4pital Timone Enfants, Assistance Publique H\u00f4pitaux de Marseille, 13915 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-2567","authenticated-orcid":false,"given":"David","family":"Cheillan","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Pathologies M\u00e9taboliques, \u00c9rythrocytaires et D\u00e9pistage P\u00e9rinatal, Service de Biochimie et Biologie Mol\u00e9culaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France"},{"name":"Laboratoire Carmen INSERM INRAE, Centre Hospitalier Lyon Sud, 69310 Pierre B\u00e9nite, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/brain\/awh712","article-title":"Clinical, pathological and genetic characterization of 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