ArticleCell death & disease2020
A novel neurodegenerative spectrum disorder in patients with MLKL deficiency.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer's disease.Molecular psychiatry · 2022Pooled it
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Review
- RIPK3 coordinates RHIM domain-dependent antiviral inflammatory transcription in neurons.Science signaling · 2025Article
- MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.Autophagy · 2025Article
- Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.The Biochemical journal · 2024Article
- SpliceProt 2.0: A Sequence Repository of Human, Mouse, and Rat Proteoforms.International journal of molecular sciences · 2024Article
- Parkinson's disease models and death signaling: what do we know until now?Frontiers in neuroanatomy · 2024Review
- A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.Nature communications · 2023Article
- MLKL deficiency protects against low-grade, sterile inflammation in aged mice.Cell death and differentiation · 2023Article
- From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors.Journal of medicinal chemistry · 2023Review
- Schwann cell necroptosis in diabetic neuropathy.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Rare catastrophes and evolutionary legacies: human germline gene variants in MLKL and the necroptosis signalling pathway.Biochemical Society transactions · 2022Review
- Integrated stress response restricts macrophage necroptosis.Life science alliance · 2022Article
- A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes.Cell death & disease · 2021Article
- MLKL: Functions beyond serving as the Executioner of Necroptosis.Theranostics · 2021Review
- A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.Nature communications · 2020Article
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 3 countries.
Funding
Abstract
Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.