NUBPL – Mitochondrial Complex I Deficiency

NUBPL encodes the nucleotide binding protein-like assembly factor essential for mitochondrial respiratory chain complex I. Autosomal recessive biallelic NUBPL variants result in mitochondrial complex I deficiency, characterized by early-onset neurological impairment, including global developmental delay, cerebellar atrophy, spasticity, seizures and intellectual disability. The phenotype is distinct yet rare, with 19 cases reported to date ([PMID:36280881]).

The first molecular diagnosis used next-generation sequencing to identify an apparent homozygous missense variant c.166G>A (p.Gly56Arg), but follow-up studies revealed compound heterozygosity for c.166G>A and a branch-site splice mutation c.815-27T>C. Causality was confirmed by lentiviral complementation of patient fibroblasts with wild-type NUBPL cDNA, emphasizing the necessity of experimental validation beyond in silico NGS predictions ([PMID:22072591]).

A subsequent multi-patient study expanded the cohort by five additional probands from four families, bringing the total to 13 genetically confirmed patients. All families harbored the recurrent branch-site c.815-27T>C allele in cis with c.166G>A or in trans with other variants: c.311T>C (p.Leu104Pro) in three patients, c.693+1G>A in one, and c.545T>C (p.Val182Ala) in one. Functional analyses included RNA-Seq transcript studies, yeast biochemical assays and mitochondrial respiration assays in patient fibroblasts, all demonstrating impaired complex I function ([PMID:32518176]).

High-throughput pooled sequencing of candidate genes in a cohort of 103 cases provided early confirmatory evidence by cDNA complementation, identifying NUBPL as a causal gene among complex I deficiency patients ([PMID:20818383]). Further yeast modeling of the homologous Ind1 protein showed that the Leu104Pro substitution destabilizes the assembly factor, leading to null-mutant phenotypes and specific cold sensitivity assays, while other variants variably disrupted complex I assembly ([PMID:29982452]).

A patient-specific knock-in mouse harboring Nubpl c.311T>C (p.Leu104Pro) demonstrated embryonic lethality of homozygotes at E10.5 and normal phenotype in heterozygotes, supporting a hypomorphic mechanism and confirming recessive inheritance without dominant effects ([PMID:36280881]).

Integrated genetic and experimental data provide strong evidence for a definitive gene–disease association. Genetic testing for NUBPL variants, including the recurrent c.815-27T>C branch-site mutation, should be considered in patients with unexplained complex I deficiency. Functional assays remain critical for variant interpretation and accurate diagnosis.

References

• Human mutation • 2012 • Next-generation sequencing in molecular diagnosis: NUBPL mutations highlight the challenges of variant detection and interpretation. PMID:22072591
• Nature genetics • 2010 • High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. PMID:20818383
• Journal of medical genetics • 2021 • NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum. PMID:32518176
• Human molecular genetics • 2018 • Pathogenic mutations in NUBPL affect complex I activity and cold tolerance in the yeast model Yarrowia lipolytica. PMID:29982452
• Orphanet journal of rare diseases • 2022 • Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice. PMID:36280881

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