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New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1

Serine palmitoyltransferase long chain base subunit 1 (SPTLC1) encodes a serine palmitoyltransferase (SPT) resident in the endoplasmic reticulum (ER). Pathological SPTLC1 variants cause a form of hereditary sensory and autonomic neuropathy (HSAN1A), and have recently been linked to unrestrained sphi...

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Autores principales: Kölbel, Heike, Kraft, Florian, Hentschel, Andreas, Czech, Artur, Gangfuss, Andrea, Mohassel, Payam, Nguyen, Chi, Stenzel, Werner, Schara-Schmidt, Ulrike, Preuße, Corinna, Roos, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140917/
https://www.ncbi.nlm.nih.gov/pubmed/35627278
http://dx.doi.org/10.3390/genes13050893
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author Kölbel, Heike
Kraft, Florian
Hentschel, Andreas
Czech, Artur
Gangfuss, Andrea
Mohassel, Payam
Nguyen, Chi
Stenzel, Werner
Schara-Schmidt, Ulrike
Preuße, Corinna
Roos, Andreas
author_facet Kölbel, Heike
Kraft, Florian
Hentschel, Andreas
Czech, Artur
Gangfuss, Andrea
Mohassel, Payam
Nguyen, Chi
Stenzel, Werner
Schara-Schmidt, Ulrike
Preuße, Corinna
Roos, Andreas
author_sort Kölbel, Heike
collection PubMed
description Serine palmitoyltransferase long chain base subunit 1 (SPTLC1) encodes a serine palmitoyltransferase (SPT) resident in the endoplasmic reticulum (ER). Pathological SPTLC1 variants cause a form of hereditary sensory and autonomic neuropathy (HSAN1A), and have recently been linked to unrestrained sphingoid base synthesis, causing a monogenic form of amyotrophic lateral sclerosis (ALS). It was postulated that the phenotypes associated with dominant variants in SPTLC1 may represent a continuum between neuropathy and ALS in some cases, complicated by additional symptoms such as cognitive impairment. A biochemical explanation for this clinical observation does not exist. By performing proteomic profiling on immortalized lymphoblastoid cells derived from one patient harbouring an alanine to serine amino acid substitution at position 20, we identified a subset of dysregulated proteins playing significant roles in neuronal homeostasis and might have a potential impact on the manifestation of symptoms. Notably, the identified p.(A20S)-SPTLC1 variant is associated with decrease of transcript and protein level. Moreover, we describe associated muscle pathology findings, including signs of mild inflammation accompanied by dysregulation of respective markers on both the protein and transcript levels. By performing coherent anti-Stokes Raman scattering microscopy, presence of protein and lipid aggregates could be excluded.
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spelling pubmed-91409172022-05-28 New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1 Kölbel, Heike Kraft, Florian Hentschel, Andreas Czech, Artur Gangfuss, Andrea Mohassel, Payam Nguyen, Chi Stenzel, Werner Schara-Schmidt, Ulrike Preuße, Corinna Roos, Andreas Genes (Basel) Article Serine palmitoyltransferase long chain base subunit 1 (SPTLC1) encodes a serine palmitoyltransferase (SPT) resident in the endoplasmic reticulum (ER). Pathological SPTLC1 variants cause a form of hereditary sensory and autonomic neuropathy (HSAN1A), and have recently been linked to unrestrained sphingoid base synthesis, causing a monogenic form of amyotrophic lateral sclerosis (ALS). It was postulated that the phenotypes associated with dominant variants in SPTLC1 may represent a continuum between neuropathy and ALS in some cases, complicated by additional symptoms such as cognitive impairment. A biochemical explanation for this clinical observation does not exist. By performing proteomic profiling on immortalized lymphoblastoid cells derived from one patient harbouring an alanine to serine amino acid substitution at position 20, we identified a subset of dysregulated proteins playing significant roles in neuronal homeostasis and might have a potential impact on the manifestation of symptoms. Notably, the identified p.(A20S)-SPTLC1 variant is associated with decrease of transcript and protein level. Moreover, we describe associated muscle pathology findings, including signs of mild inflammation accompanied by dysregulation of respective markers on both the protein and transcript levels. By performing coherent anti-Stokes Raman scattering microscopy, presence of protein and lipid aggregates could be excluded. MDPI 2022-05-17 /pmc/articles/PMC9140917/ /pubmed/35627278 http://dx.doi.org/10.3390/genes13050893 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kölbel, Heike
Kraft, Florian
Hentschel, Andreas
Czech, Artur
Gangfuss, Andrea
Mohassel, Payam
Nguyen, Chi
Stenzel, Werner
Schara-Schmidt, Ulrike
Preuße, Corinna
Roos, Andreas
New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
title New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
title_full New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
title_fullStr New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
title_full_unstemmed New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
title_short New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
title_sort new insights into the neuromyogenic spectrum of a gain of function mutation in sptlc1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140917/
https://www.ncbi.nlm.nih.gov/pubmed/35627278
http://dx.doi.org/10.3390/genes13050893
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