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  • 1
    Online Resource
    Online Resource
    Phenotypical and Myopathological Consequences of Compound Heterozygous Missense and Nonsense Variants in SLC18A3
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 12 ( 2021-12-09), p. 3481-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 12 ( 2021-12-09), p. 3481-
    Abstract: Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Methods: Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. Results: ES unraveled compound heterozygous missense and nonsense variants (c.315G 〉 A, p.Trp105* and c.1192G 〉 C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to a more severe effect of the nonsense variant. Therapy with pyridostigmine was only partially effective while 3,4 diaminopyridine showed no effect. Microscopic investigation of the muscle biopsy revealed reduced fibre size and a significant accumulation of lipid droplets. Conclusions: We suggest that nonsense variants have a more detrimental impact on the clinical manifestation of SLC18A3-associated CMS. The impact of pathogenic SLC18A3 variants on muscle fibre integrity beyond the effect of denervation is suggested by the build-up of lipid aggregates. This in turn implicates the importance of proper VAChT-mediated synthesis and recycling of ACh for lipid homeostasis in muscle cells. This hypothesis is further supported by the pathological observations obtained in previously published VAChT-animal models.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10123481
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2661518-6
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  • 2
    Online Resource
    Online Resource
    Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement
    Wiley ; 2022
    In:  The Journal of Pathology Vol. 256, No. 1 ( 2022-01), p. 93-107
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    In: The Journal of Pathology, Wiley, Vol. 256, No. 1 ( 2022-01), p. 93-107
    Abstract: Recessive variants in WASHC4 are linked to intellectual disability complicated by poor language skills, short stature, and dysmorphic features. The protein encoded by WASHC4 is part of the Wiskott–Aldrich syndrome protein and SCAR homolog family, co‐localizes with actin in cells, and promotes Arp2/3‐dependent actin polymerization in vitro . Functional studies in a zebrafish model suggested that WASHC4 knockdown may also affect skeletal muscles by perturbing protein clearance. However, skeletal muscle involvement has not been reported so far in patients, and precise biochemical studies allowing a deeper understanding of the molecular etiology of the disease are still lacking. Here, we report two siblings with a homozygous WASHC4 variant expanding the clinical spectrum of the disease and provide a phenotypical comparison with cases reported in the literature. Proteomic profiling of fibroblasts of the WASHC4‐deficient patient revealed dysregulation of proteins relevant for the maintenance of the neuromuscular axis. Immunostaining on a muscle biopsy derived from the same patient confirmed dysregulation of proteins relevant for proper muscle function, thus highlighting an affliction of muscle cells upon loss of functional WASHC4. The results of histological and coherent anti‐Stokes Raman scattering microscopic studies support the concept of a functional role of the WASHC4 protein in humans by altering protein processing and clearance. The proteomic analysis confirmed key molecular players in vitro and highlighted, for the first time, the involvement of skeletal muscle in patients. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.v256.1
    DOI: 10.1002/path.5812
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1475280-3
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  • 3
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    Online Resource
    Protein signature of human skin fibroblasts allows the study of the molecular etiology of rare neurological diseases
    Springer Science and Business Media LLC ; 2021
    In:  Orphanet Journal of Rare Diseases Vol. 16, No. 1 ( 2021-12)
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    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2021-12)
    Abstract: The elucidation of pathomechanisms leading to the manifestation of rare (genetically caused) neurological diseases including neuromuscular diseases (NMD) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these “discovery studies” are often limited by the availability of human biomaterial. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. Methods Human skin fibroblasts were used to generate a spectral library using pH8-fractionation of followed by nano LC-MS/MS. Afterwards, Allgrove-patient derived fibroblasts were subjected to a data independent acquisition approach. In addition, proteomic signature of an enriched nuclear protein fraction was studied. Proteomic findings were confirmed by immunofluorescence in a muscle biopsy derived from the same patient and cellular lipid homeostasis in the cause of Allgrove syndrome was analysed by fluorescence (BODIPY-staining) and coherent anti-Stokes Raman scattering (CARS) microscopy. Results To systematically address the question if human skin fibroblasts might serve as valuable biomaterial for (molecular) studies of NMD, we generated a protein library cataloguing 8280 proteins including a variety of such linked to genetic forms of motoneuron diseases, congenital myasthenic syndromes, neuropathies and muscle disorders. In silico-based pathway analyses revealed expression of a diversity of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMD. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMD by a use case: the proteomic signature of fibroblasts derived from an Allgrove-patient was studied. Dysregulation of paradigmatic proteins could be confirmed in muscle biopsy of the patient and protein-functions could be linked to neurological symptoms known for this disease. Moreover, proteomic investigation of nuclear protein composition allowed the identification of protein-dysregulations according with structural perturbations observed in the muscle biopsy. BODIPY-staining on fibroblasts and CARS microscopy on muscle biopsy suggest altered lipid storage as part of the underlying disease etiology. Conclusions Our combined data reveal that human fibroblasts may serve as an in vitro system to study the molecular etiology of rare neurological diseases exemplified on Allgrove syndrome in an unbiased fashion.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-020-01669-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2225857-7
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  • 4
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    Online Resource
    New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
    MDPI AG ; 2022
    In:  Genes Vol. 13, No. 5 ( 2022-05-17), p. 893-
    Details
    In: Genes, MDPI AG, Vol. 13, No. 5 ( 2022-05-17), p. 893-
    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.
    Type of Medium: Online Resource
    ISSN: 2073-4425
    URL: Article
    DOI: 10.3390/genes13050893
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527218-4
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