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

Abstract

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.

The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases

“…This gene encodes for a subunit of SPT, the enzyme required for the first step of SL synthesis. C-terminal SPTLC1 variants cause the formation of atypical deoxysphingolipids and result in HSAN1 [94]. The ALS-causing variants map to a transmembrane domain, which interacts with negative regulators of SPT activity and results in unregulated SPT and excess SL synthesis [95].…”

Proteomic studies in VWA1‐related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers

“…Functional and biochemical research of neurological illnesses is often limited by the availability of appropriate biomaterial. Notably, patient‐derived white blood cells have been shown to represent suitable in vitro models to study the nature of rare neurological disorders overcoming the scarcity of tissues vulnerable in these diseases 10–12 . Thus, here in the context of the first biomarker study of VWA1 ‐related neuromyopathy, we investigated white blood cells to define marker proteins with pathophysiological relevance in skeletal muscle as a tissue clinically affected by the presence of pathogenic VWA1 ‐variants.…”

“…Notably, patient‐derived white blood cells have been shown to represent suitable in vitro models to study the nature of rare neurological disorders overcoming the scarcity of tissues vulnerable in these diseases. 10 , 11 , 12 Thus, here in the context of the first biomarker study of VWA1 ‐related neuromyopathy, we investigated white blood cells to define marker proteins with pathophysiological relevance in skeletal muscle as a tissue clinically affected by the presence of pathogenic VWA1 ‐variants. For that purpose, proteomic profiling was carried out on white blood cells derived from six VWA1 ‐patients of two unrelated families.…”

Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity

“…Mutations that result in partial loss of ASAH1 activity are associated with non-5q spinal muscular atrophy, and morpholino knockdown of ASAH1 in zebrafish leads to a loss of motor neuron axons, further bolstering evidence that ceramide accumulation triggers neurodegeneration (Zhou et al, 2012). Interestingly, SPTLC1 (an SPT complex member) gain of function mutations that increase ceramide synthesis also lead to motor neuron disease in children (Johnson et al, 2021; Kölbel et al, 2022; Mohassel et al, 2021). Moreover, mutations in SPTLC that result in deoxysphingolipid accumulation lead to Hereditary Sensory and Autonomic Neuropathy Type I (HSAN-I), a disease with sensory loss and distal muscle weakness (Dawkins et al, 2001; Kölbel et al, 2022; Penno et al, 2010).…”

“…Interestingly, SPTLC1 (an SPT complex member) gain of function mutations that increase ceramide synthesis also lead to motor neuron disease in children (Johnson et al, 2021;Kölbel et al, 2022;Mohassel et al, 2021). Moreover, mutations in SPTLC that result in deoxysphingolipid accumulation lead to Hereditary Sensory and Autonomic Neuropathy Type I (HSAN-I), a disease with sensory loss and distal muscle weakness (Dawkins et al, 2001;Kölbel et al, 2022;Penno et al, 2010). On the other hand, loss of function of DEGS1 disrupts ceramide de novo synthesis and leads to hypomyelinating leukodystrophy type 18 (HDL18) (Pant et al, 2019;Planas-Serra et al, 2023), illustrating the importance of precise ceramide synthesis regulation for brain development and function.…”