ArticleGenetics in medicine : official journal of the American College of Medical Genetics2024
Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Disruptions in RNA Splicing: A Key Regulator of Cognitive Impairment in Perioperative Neurocognitive Disorders.Neuroscience bulletin · 2026Review
- Time-Restricted Feeding Alters Behavior in a Sex-Specific Manner in Mice With Neuropathic Pain.Molecular nutrition & food research · 2026Article
- Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.International journal of molecular sciences · 2026Article
- Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.Brain : a journal of neurology · 2026Article
- Comparative effects of standardized Centella asiatica extract (ECa 233) and its active compound mixture on proteomics and mitochondrial function.Scientific reports · 2025Article
- Gene therapy prevents onset of mitochondrial cardiomyopathy in neonatal mice with Ndufs6 deficiency.Cell death discovery · 2025Article
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23 authors.
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Abstract
purposeWe describe 3 families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome. We aimed to characterize clinically and molecularly the newly identified patients and understand the mechanism underlying their milder phenotype.
methodsThe patients underwent extensive clinical examinations. Exome sequencing was done in 4 affected individuals. The functional effect of the c.309+5G>A variant was investigated in patient-derived EBV-transformed lymphoblasts at the complementary DNA, protein, and mitochondrial level. Alternative splicing was evaluated using complementary DNA long-read sequencing.
resultsAll patients presented with early-onset, slowly progressive axonal CMT, and nystagmus; some exhibited additional central nervous system symptoms. The c.309+5G>A substitution caused the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Immunoblotting showed reduced levels of mutant isoforms. No detectable defects in mitochondrial complex stability or bioenergetics were found.
conclusionWe expand the clinical spectrum of NDUFS6-related mitochondrial disorders to include axonal CMT, emphasizing the clinical and pathophysiologic overlap between these 2 clinical entities. This work demonstrates the critical role that alternative splicing may play in modulating the severity of a genetic disorder, emphasizing the need for careful consideration when interpreting splice variants and their implications on disease prognosis.
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