NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern
Sietske H Kevelam1, Richard J Rodenburg, Nicole I Wolf
1Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.
Objective:
To identify the mutated gene in a group of patients with an unclassified heritable white matter disorder sharing the same, distinct MRI pattern.
Methods:
We used MRI pattern recognition analysis to select a group of patients with a similar, characteristic MRI pattern. We performed whole-exome sequencing to identify the mutated gene. We examined patients' fibroblasts for biochemical consequences of the mutant protein.
Results:
We identified 6 patients from 5 unrelated families with a similar MRI pattern showing predominant abnormalities of the cerebellar cortex, deep cerebral white matter, and corpus callosum. The 4 tested patients had a respiratory chain complex І deficiency. Exome sequencing revealed mutations in NUBPL, encoding an iron-sulfur cluster assembly factor for complex І, in all patients. Upon identification of the mutated gene, we analyzed the MRI of a previously published case with NUBPL mutations and found exactly the same pattern. A strongly decreased amount of NUBPL protein and fully assembled complex I was found in patients' fibroblasts. Analysis of the effect of mutated NUBPL on the assembly of the peripheral arm of complex I indicated that NUBPL is involved in assembly of iron-sulfur clusters early in the complex I assembly pathway.
Conclusion:
Our data show that NUBPL mutations are associated with a unique, consistent, and recognizable MRI pattern, which facilitates fast diagnosis and obviates the need for other tests, including assessment of mitochondrial complex activities in muscle or fibroblasts.
Insights
Mutations in the NUBPL gene cause a distinct white matter disorder identifiable by MRI. This finding aids in rapid diagnosis of this rare neurological condition.
Area of Science:
- Neurogenetics
- Neuroimaging
- Mitochondrial Biology
Background:
- Unclassified heritable white matter disorders present diagnostic challenges.
- Distinct neuroimaging patterns can indicate specific genetic causes.
- Mitochondrial respiratory chain complex deficiencies are linked to neurological dysfunction.
Purpose of the Study:
- To identify the genetic cause of a rare white matter disorder with a characteristic MRI pattern.
- To investigate the role of NUBPL in mitochondrial complex I assembly.
Main Methods:
- MRI pattern recognition to select patient cohorts.
- Whole-exome sequencing for mutation identification.
- Fibroblast analysis to assess biochemical consequences of mutations.
Main Results:
- Identified NUBPL mutations in 6 patients from 5 families with a consistent MRI pattern.
- Patients exhibited respiratory chain complex I deficiency.
- NUBPL mutations impair iron-sulfur cluster assembly in complex I.
Conclusions:
- NUBPL mutations are associated with a unique and recognizable MRI pattern.
- This MRI pattern facilitates rapid diagnosis of NUBPL-related disorders.
- Diagnosis can be made without invasive biochemical testing.
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