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

Abstract

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.

Reverse Genetic Screen for Deleterious Recessive Variants in the Local Simmental Cattle Population of Switzerland

“…More precisely, the NUBPL supplies Fe/S clusters to the respiratory complex I and thereby ensures that important subunits are delivered to build the whole complex [ 70 ]. In human, pathogenic variants affecting NUBPL are associated with the autosomal recessive mitochondrial complex I deficiency disorder (OMIM: 613621, 618242) [ 71 , 72 , 73 ]. These variants include missense, frameshift and splice site variants, as well as small and large insertions and deletions.…”

“…These variants include missense, frameshift and splice site variants, as well as small and large insertions and deletions. Clinical symptoms of mitochondrial complex I deficiency include, among others, ataxia, dysarthria, hypotonia, nystagmus, spasticity, and tremor [ 73 ]. Furthermore, variants in NUBPL were hypothesized as risk factors for Parkinson’s disease [ 74 ].…”

Molecular Basis of Rare Diseases Associated to the Maturation of Mitochondrial [4Fe-4S]-Containing Proteins

“…Five missense ( Table 1 ) and four non-missense disease-causing variants in IND1 (also named NUBPL) have been identified to date in patients affected by complex I deficiency. The amount of IND1 protein and of fully assembled complex I was strongly reduced in patients’ fibroblasts [ 91 , 94 ]. Clinical features include onset of neurological symptoms at the age of 3–18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity.…”

“…Two other pathogenic mutations, i.e., Leu104Pro and Val182Ala, are located on two adjacent parallel β-strands on the opposite side of the β-sheet where Asp105 is located ( Figure 9 B). p.Leu104Pro variant was found in trans with the c.815-27T > C branch-site mutation in three patients [ 94 ]. Clinical features include onset of neurological symptoms at the age of 3–18 months, general developmental delay, spasticity, ataxia, nystagmus and tremor.…”

“…Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity. Biochemical studies in a yeast model showed reduced complex I function [ 94 ]. p.Val182Ala variant was found in trans with the c.815-27T > C branch-site mutation in one patient [ 94 ].…”