title: NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Sietske H
authors.initials: SH
authors.lastname: Kevelam
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Wolf
authors.forename: Patrick
authors.initials: P
authors.lastname: Ferreira
authors.forename: Roelineke J
authors.initials: RJ
authors.lastname: Lunsing
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Anne
authors.initials: A
authors.lastname: Mitchell
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Arroyo
authors.forename: Dietz
authors.initials: D
authors.lastname: Rating
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.forename: Carola G M
authors.initials: CG
authors.lastname: van Berkel
authors.forename: Truus E M
authors.initials: TE
authors.lastname: Abbink
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation
chemical_list: D024101:Mitochondrial Proteins; C572056:NUBPL protein, human; D042967:Electron Transport Complex I
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