Complex I deficiency has been reported for at least 38 of 44 complex I genes. The NUBPL gene is an assembly factor, a subclass of 16 complex I genes, and 12 have been reported to cause this recessive disorder. Of 15 reported families with at least one patient with NUBPL Complex I deficiency, 12 were found to be compound heterozygotes for the splicing mutation c.815-27T>C plus a second mutation (deletion, missense, or another splicing variant). The c.815-27T>C splicing variant, which causes exon skipping, is relatively common in European ancestry subjects (allele frequency is 0.004476 in non-Finnish Europeans and 0.01241 in Finnish). Other pathogenic NUBPL variants observed in more than one patient are the missense variant c.311T>C [p.L104P] (4 families) and the splicing variant c.693+1G>A (3 families). Patients without the c.815-27T>C variant (3 families reported, see Kimonis et al. (2021) and references therein) appear to have some of the same symptoms (e.g., tremor and spasticity) but other clinical features have been reported (e.g., bilateral striatal necrosis, dystonia, and thalamic involvement). Since diagnostic testing with biochemical assays (e.g., for electron transport chain defects) are often negative, whole exome sequencing (WES) or whole genome sequencing (WGS) should be the primary means to confirm a diagnosis of NUBPL Complex I deficiency. Chromosomal microarray analysis (CMA) may also aid in the diagnosis as the genome for the first reported patient harbored a chromosomal rearrangement that disrupted NUBPL. A follow up report on this patient confirmed that the second pathogenic variant was c.815-27T>C, rather than originally suspected missense variant c.166G>A [p.G56R], which is often found on the same haplotype as c.815-27T>C but functional experiments have thus far not confirmed its pathogenicity despite a deleterious prediction (e.g., via CADD, PolyPhen, and SIFT). We also note that the Calvo et al. (2010) chromosomal rearrangement has been found in a Parkinson’s patient; see Research collaboration for further details.
Cheng et al. (2022) generated a knock-in mouse harboring a patient-specific variant of Nubpl (c.311T>C; p. L104P) that was reported in three families. The heterozygote mice did not manifest any significant behavioral and or pathological changes for alpha-synuclein and oxidative stress markers compared to control mice. Similar to Nubpl global knockout mice, the Nubpl L104P homozygous mice are lethal at embryonic day E10.5, suggesting that the Nubpl L104P variant is likely a hypomorph allele.
NUBPL