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  • 1
    Online Resource
    Online Resource
    SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 4 ( 2023-04-19), p. 1420-1435
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 4 ( 2023-04-19), p. 1420-1435
    Abstract: Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila. Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila. These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac460
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    detail.hit.zdb_id: 80072-7
    SSG: 12
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Epidemiology and transmission dynamics of COVID-19 in two Indian states
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 370, No. 6517 ( 2020-11-06), p. 691-697
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 370, No. 6517 ( 2020-11-06), p. 691-697
    Abstract: Although most cases of coronavirus disease 2019 (COVID-19) have occurred in low-resource countries, little is known about the epidemiology of the disease in such contexts. Data from the Indian states of Tamil Nadu and Andhra Pradesh provide a detailed view into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission pathways and mortality in a high-incidence setting. Reported cases and deaths have been concentrated in younger cohorts than would be expected from observations in higher-income countries, even after accounting for demographic differences across settings. Among 575,071 individuals exposed to 84,965 confirmed cases, infection probabilities ranged from 4.7 to 10.7% for low-risk and high-risk contact types, respectively. Same-age contacts were associated with the greatest infection risk. Case fatality ratios spanned 0.05% at ages of 5 to 17 years to 16.6% at ages of 85 years or more. Primary data from low-resource countries are urgently needed to guide control measures.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abd7672
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    SSG: 11
    Location Call Number Limitation Availability
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