Armirola-Ricaurte, C;
Zonnekein, N;
Koutsis, G;
Amor-Barris, S;
Pelayo-Negro, AL;
Atkinson, D;
Efthymiou, S;
... Jordanova, A; + view all
(2024)
Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.
Genetics in Medicine
, 26
(6)
, Article 101117. 10.1016/j.gim.2024.101117.
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Abstract
PURPOSE: We 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. METHODS: The 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. RESULTS: All 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. CONCLUSION: We 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.
| Type: | Article |
|---|---|
| Title: | Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.gim.2024.101117 |
| Publisher version: | http://dx.doi.org/10.1016/j.gim.2024.101117 |
| Language: | English |
| Additional information: | © 2024 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Charcot-Marie-Tooth, Mitochondrial disorders, NDUFS6, Peripheral neuropathy, Splicing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10191565 |
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