scholarly journals Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model

2013 ◽  
Vol 6 (5) ◽  
pp. 1279-1284 ◽  
Author(s):  
M. M. Wydro ◽  
J. Balk
Keyword(s):  
Mitochondrial Disease ◽  
Complex I ◽  
Site Mutation ◽  
Branch Site ◽  
Complex I Deficiency ◽  
Yeast Model

scholarly journals Investigating complex I deficiency in P urkinje cells and synapses in patients with mitochondrial disease

2015 ◽  
Vol 42 (5) ◽  
pp. 477-492 ◽  
Author(s):  
Alexia Chrysostomou ◽  
John P. Grady ◽  
Alex Laude ◽  
Robert W. Taylor ◽  
Doug M. Turnbull ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Complex I ◽  
Complex I Deficiency

scholarly journals RNA sequencing identifies a cryptic exon caused by a deep intronic variant in NDUFB10 resulting in isolated Complex I deficiency.

2020 ◽  
Author(s):  
Guy Helman ◽  
Alison G. Compton ◽  
Daniella H. Hock ◽  
Marzena Walkiewicz ◽  
Gemma R. Brett ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Mitochondrial Disease ◽  
Complex I ◽  
Differential Expression Analysis ◽  
Single Individual ◽  
Poor Growth ◽  
Cryptic Exon ◽  
Complex I Deficiency ◽  
Oxphos Complex ◽  
Older Sibling

The diagnosis of mitochondrial disorders remains a challenging and often unmet need. We sought to investigate a sibling pair with suspected mitochondrial disease and a clinical presentation notable for global developmental delay, poor growth, sensorineural hearing loss, and brain MRI abnormalities, both with early death. Following uninformative exome and genome sequencing of the family quartet, RNA sequencing was pursued as an orthogonal testing strategy. RNA sequencing of fibroblasts from the older sibling identified the presence of a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. NDUFB10 encodes a subunit of mitochondrial OXPHOS complex I. Differential expression analysis relative to control samples suggested significantly decreased expression. The cryptic exon was found to contain a rare intronic variant, NM_004548.3:c.131-442G>C, that was homozygous in both affected siblings and absent from population allele frequency databases. Immunoblot and quantitative proteomic analysis of fibroblasts from the older sibling revealed decreased abundance of complex I subunits associated with NDUFB10, providing evidence of isolated complex I deficiency. Biallelic variants in NDUFB10 have previously been reported in a single individual with infantile-onset mitochondrial disease. We present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two further individuals. This variant results in loss of expression and overall destabilization of mitochondrial OXPHOS complex I and highlights the importance of RNA sequencing as a complementary diagnostic tool in patients undergoing genome-wide diagnostic evaluation.

scholarly journals Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle

Neurology ◽  
1996 ◽  
Vol 47 (1) ◽  
pp. 243-248 ◽  
Author(s):  
H. A.C.M. Bentlage ◽  
U. Wendel ◽  
H. Schagger ◽  
H. J. ter Laak ◽  
A.J.M. Janssen ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Complex I ◽  
Complex I Deficiency

scholarly journals NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum

2020 ◽  
pp. jmedgenet-2020-106846
Author(s):  
Virginia Kimonis ◽  
Rehab al Dubaisi ◽  
Andrew E Maclean ◽  
Kathy Hall ◽  
Lan Weiss ◽  
...  
Keyword(s):  
Complex I ◽  
Phenotypic Variability ◽  
Brain Mri ◽  
Mitochondrial Disorder ◽  
Cerebellar Atrophy ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Yeast Model

BackgroundThe nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).MethodsWhole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts.ResultsThe previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3–18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.ConclusionWe report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.

scholarly journals Novel MT-ND Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency

2020 ◽  
Vol 11 ◽  
Author(s):  
Yi Shiau Ng ◽  
Kyle Thompson ◽  
Daniela Loher ◽  
Sila Hopton ◽  
Gavin Falkous ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Complex I ◽  
Gene Variants ◽  
Adult Onset ◽  
Complex I Deficiency

scholarly journals TAT-Conjugated NDUFS8 Can Be Transduced into Mitochondria in a Membrane-Potential-Independent Manner and Rescue Complex I Deficiency

2021 ◽  
Vol 22 (12) ◽  
pp. 6524
Author(s):  
Bo-Yu Lin ◽  
Gui-Teng Zheng ◽  
Kai-Wen Teng ◽  
Juan-Yu Chang ◽  
Chao-Chang Lee ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Fusion Proteins ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Leigh Syndrome ◽  
Protein Transduction ◽  
Independent Manner ◽  
Complex I Deficiency ◽  
Transactivator Of Transcription ◽  
Hiv 1

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. In this study, we developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects. Two fusion proteins (TAT-NDUFS8 and NDUFS8-TAT) were exogenously expressed and purified from Escherichia coli for transduction of human cells. In addition, similar constructs were generated and used in transfection studies for comparison. The results showed that both exogenous TAT-NDUFS8 and NDUFS8-TAT were delivered into mitochondria and correctly processed. Interestingly, the mitochondrial import of TAT-containing NDUFS8 was independent of mitochondrial membrane potential. Treatment with TAT-NDUFS8 not only significantly improved the assembly of complex I in an NDUFS8-deficient cell line, but also partially rescued complex I functions both in the in-gel activity assay and the oxygen consumption assay. Our current findings suggest the considerable potential of applying the TAT-mediated protein transduction system for treatment of complex I deficiency.

Sign in / Sign up

Export Citation Format

Share Document