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1.
J Neurol Neurosurg Psychiatry ; 95(3): 201-205, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38041684

RESUMEN

BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS. SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex. METHODS: We used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants in SPTLC2. The de-novo status was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry. RESULTS: Two unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novel de-novo SPTLC2 mutation, c.203T>G, p.Met68Arg. This variant lies within a single short transmembrane domain of SPTLC2, suggesting that the mutation renders the SPT complex irresponsive to regulation through ORMDL3. Confirming this hypothesis, ceramide and complex sphingolipid levels were significantly increased in patient plasma. Accordingly, excessive sphingolipid production was shown in mutant-expressing human embryonic kindney (HEK) cells. CONCLUSIONS: Specific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.


Asunto(s)
Esclerosis Amiotrófica Lateral , Serina C-Palmitoiltransferasa , Humanos , Esclerosis Amiotrófica Lateral/genética , Ceramidas , Mutación con Ganancia de Función , Mutación/genética , Serina C-Palmitoiltransferasa/genética , Serina C-Palmitoiltransferasa/química , Esfingolípidos
2.
J Hum Genet ; 64(11): 1141-1144, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31420593

RESUMEN

Distal hereditary motor neuronopathies (dHMN) are a genetically heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and progressive distal muscle weakness. A heterozygous missense variant in FBXO38 has been previously described in two families affected by autosomal-dominant dHMN. In this paper, we describe a homozygous missense variant in FBXO38 (c.1577G>A; p.(Arg526Gln)) in a young Turkish female, offspring of consanguineous parents, with a congenital mild neuronopathy with idiopathic toe walking, normal sensory examination, and hearing loss. This work is the first to describe a novel homozygous variant and a suggested loss of function mechanism in FBXO38, expanding the dHMN type IID phenotype.


Asunto(s)
Proteínas F-Box/genética , Atrofia Muscular Espinal/genética , Adulto , Femenino , Heterogeneidad Genética , Heterocigoto , Homocigoto , Humanos , Atrofia Muscular Espinal/fisiopatología , Mutación Missense/genética , Linaje , Fenotipo , Adulto Joven
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