ArticleDisease models & mechanisms2014
LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition.
Article in Disease models & mechanisms, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 27 citations in OpenAlex.
- Elevated levels of Letm1 drives mitochondrial dysfunction and cardiomyocyte stress-mediated apoptosis in cultured cardiomyocytes.Cell communication and signaling : CCS · 2025Article
- Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.American journal of human genetics · 2022Article
- Emerging role of LETM1/GRP78 axis in lung cancer.Cell death & disease · 2022Article
- Mitochondrial calcium exchange in physiology and disease.Physiological reviews · 2022Review
- Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- LETM1: A Single Entity With Diverse Impact on Mitochondrial Metabolism and Cellular Signaling.Frontiers in physiology · 2021Review
- LETM1 Promotes Gastric Cancer Cell Proliferation, Migration, and Invasion via the PI3K/Akt Signaling Pathway.Journal of gastric cancer · 2020Article
- LETM1 couples mitochondrial DNA metabolism and nutrient preference.EMBO molecular medicine · 2018Article
- Cytogenomic Integrative Network Analysis of the Critical Region Associated with Wolf-Hirschhorn Syndrome.BioMed research international · 2018Article
- Loss of forebrain MTCH2 decreases mitochondria motility and calcium handling and impairs hippocampal-dependent cognitive functions.Scientific reports · 2017Article
- LETM1-Mediated KFrontiers in physiology · 2017Article
- Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome.Journal of medical genetics · 2016Article
- Essential role of mitochondrial Ca2+ uniporter in the generation of mitochondrial pH gradient and metabolism-secretion coupling in insulin-releasing cells.The Journal of biological chemistry · 2015Article
- LETM1 overexpression is correlated with the clinical features and survival outcome of breast cancer.International journal of clinical and experimental pathology · 2015Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 4 countries.
Funding
Abstract
Wolf-Hirschhorn syndrome (WHS) represents an archetypical example of a contiguous gene deletion disorder - a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are major co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes a mitochondrial inner-membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism, principally for seizures but also for other core features of WHS, including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from individuals with WHS. Here, using a unique panel of WHS-patient-derived cell lines with deletions of differing sizes, incorporating LETM1 or not, we show, for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS-patient cells. Furthermore, we show that this is associated with distinct mitochondrial phenotypes, including altered intracellular [Ca(2+)] levels, dysfunctional mitochondrial transition-pore opening, hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression level; these phenotypes could underlie and/or contribute to some of the core clinical features of this condition.
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