Abstract
In an unbiased genome-wide screen for copy number variants (CNVs) on a cohort of Parkinson's disease (PD) patients, we identified in one patient a complex chromosomal rearrangement involving the nucleotide binding protein-like (NUBPL) gene on chromosome 14q12. We noted that mutations in the NUBPL gene had been reported as causing autosomal recessive (AR) mitochondrial Complex I (CI) deficiency in children. The precise breakpoints of the rearrangement in our PD case were found to be identical to those described in a patient with AR CI deficiency who also harbored a second pathogenic mutation in NUBPL. Mitochondrial dysfunction has long been considered a strong contributor to PD, and there is substantial evidence that decreased CI activity plays a central role in PD pathogenesis. We hypothesize that pathogenic NUBPL variants may increase the risk for PD analogous to variants in the glucosylceramidase beta (GBA) gene that increase the risk of developing PD in heterozygous carriers.
Highlights
Mitochondrial dysfunction is a hallmark pathology of Parkinson’s disease (PD), reduced complex I (CI) activity [1, 2]
For the first time, a PD patient who carries a loss-of-function variant impacting the CI gene nucleotide binding protein-like (NUBPL; gene aliases IND1, huInd1, C14orf127), which codes for an iron-sulfur (Fe/S) assembly protein
We performed a genome-wide array comparative genomic hybridization screen of 466 PD cases and 1,000 controls to detect copy number variants (CNVs) that could contribute to PD risk
Summary
Mitochondrial dysfunction is a hallmark pathology of Parkinson’s disease (PD), reduced complex I (CI) activity [1, 2]. Despite the biochemical evidence for impaired CI activity, and accumulation of mitochondrial DNA mutations in sporadic PD [3, 4], no pathogenic variants impacting nuclear CI genes have been reported in PD. CI deficiency, a rare early-onset disorder, is known to occur via a recessive or X-linked mechanism for 33 nuclear-encoded CI genes. There is considerable genetic evidence that mutations impacting both alleles for CI genes result in severe phenotypes, but it is not known if heterozygous carriers of CI gene mutations may have an increased risk for late-onset neurodegenerative disorders such as PD. We propose that carriers of NUBPL mutations may have an increased risk for developing PD
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