In a patient with mitochondrial complex I deficiency nuclear type 21 (MC1DN21; 618242), Calvo et al. (2010) identified compound heterozygosity for 2 alleles of the NUBPL gene. One allele, inherited from the patient's father, carried a c.166G-A transition in exon 2, resulting in a gly56-to-arg (G56R) substitution, and a c.815-27T-C transition that was predicted to ablate a consensus branch sequence and resulted in the skipping of exon 10. The exon-skipping mutation was found in 2 of 232 control chromosomes from persons of European ancestry. The second allele, inherited from the patient's mother, carried a complex rearrangement interrupting NUBPL, including a 240-kb deletion spanning exons 1 through 4 and a 130-kb duplication involving exon 7 (613621.0002). The patient reported by Calvo et al. (2010) presented at 2 years of age with developmental delay, particularly of motor skills. He never achieved independent walking. He developed myopathy, nystagmus, ataxia, upper motor neuron signs, and absence seizures. Brain MRI showed leukodystrophy with involvement of the cerebellar cortex and deep white matter. At age 8, he had spasticity, ataxia, and speech problems. Patient fibroblasts had only 19% residual complex I activity on spectrophometric enzyme assay and 40% residual activity using dipstick assay. Transduction of patient fibroblasts with wildtype NUBPL restored complex I activity.
By RT-PCR analysis, Tucker et al. (2012) demonstrated that the c.815-27T-C mutation caused aberrant splicing and the generation of 3 NUBPL transcripts, 2 of which resulted in a frameshift: Gly272ValfsTer11 and Asp273GlnfsTer31; the former transcript was subject to nonsense-mediated mRNA decay. The third band represented some wildtype transcript. Cells from the patient reported by Calvo et al. (2010) had only 15% wildtype transcript and no detectable protein, whereas cells from a control who carried a heterozygous c.815-27T-C mutation had 59% protein expression. These findings indicated that the splice site mutation results in reduced NUBPL mRNA and protein expression. In addition, in vitro studies showed that the G56R protein had normal mitochondrial import and processing, was stable, and restored complex I activity in NUBPL-deficient cells. Tucker et al. (2012) concluded that the splice site mutation, although present in controls, is likely pathogenic, and that the G56R variant is unlikely to be pathogenic. However, it remained possible that the 2 variants act together to impair protein function when inherited on the same allele. The authors emphasized the importance of functional studies to assess the pathogenicity of identified variants.
Kevelam et al. (2013) identified the c.815-27T-C/R56G allele in 6 patients from 5 unrelated families with complex I deficiency and a characteristic leukoencephalopathic pattern on brain MRI. One patient from Argentina carried the complex allele in homozygous state, whereas the other patients were compound heterozygous for this allele and another presumably pathogenic variant in the NUBPL gene on the other allele (613621.0003-613621.0006). The splice site variant was found in 1 of 60 controls.
In a patient (patient 2) with MC1DN21, Kimonis et al. (2021) identified compound heterozygosity for 2 mutations in the NUBPL gene: c.815-27T-C/R56G and c.693+1G-A (613621.0005). In another patient (patient 3) with MC1DN21, Kimonis et al. (2021) identified c.815-27T-C/R56G and leu104-to-pro (L104P; 613621.0009). The mutations in both cases were identified by whole-exome sequencing, and the parents were shown to be mutation carriers.
