A Novel Mutation Associated with Neonatal Lethal Cardiomyopathy Leads to an Alternative Transcript Expression in the X-Linked Complex I NDUFB11 Gene

Int J Mol Sci. 2023 Jan 16;24(2):1743. doi: 10.3390/ijms24021743.

Abstract

We report a neonatal patient with hypertrophic cardiomyopathy (HCM), lactic acidosis and isolated complex I deficiency. Using a customized next-generation sequencing panel, we identified a novel hemizygous variant c.338G>A in the X-linked NDUFB11 gene that encodes the NADH: ubiquinone oxidoreductase subunit B11 of the mitochondrial respiratory chain (MRC) complex I (CI). Molecular and functional assays performed in the proband’s target tissues—skeletal and heart muscle—showed biochemical disturbances of the MRC, suggesting a pathogenic role for this variant. In silico analyses initially predicted an amino acid missense change p.(Arg113Lys) in the NDUFB11 CI subunit. However, we showed that the molecular effect of the c.338G>A variant, which is located at the last nucleotide of exon 2 of the NDUFB11 gene in the canonical ‘short’ transcript (sized 462 bp), instead causes a splicing defect triggering the up-regulation of the expression of an alternative ‘long’ transcript (sized 492 bp) that can also be detected in the control individuals. Our results support the hypothesis that the canonical ‘short’ transcript is required for the proper NDUFB11 protein synthesis, which is essential for optimal CI assembly and activity, whereas the longer alternative transcript seems to represent a non-functional, unprocessed splicing intermediate. Our results highlight the importance of characterizing the molecular effect of new variants in the affected patient’s tissues to demonstrate their pathogenicity and association with the clinical phenotypes.

Keywords: NDUFB11 gene; heart muscle; mitochondrial complex I; neonatal cardiomyopathy; skeletal muscle; splicing.

MeSH terms

  • Cardiomyopathies* / genetics
  • Cardiomyopathy, Hypertrophic* / genetics
  • Cardiomyopathy, Hypertrophic* / pathology
  • Electron Transport Complex I / genetics
  • Humans
  • Mitochondrial Diseases* / genetics
  • Mutation
  • Pedigree

Substances

  • Electron Transport Complex I
  • NDUFB11 protein, human

Grants and funding

This research was funded by Instituto de Salud Carlos III, (ISCIII); Ministerio de Ciencia e Innovación (Madrid, Spain), (co-funded by European Regional Development Fund “A way to make Europe”) grant number PI18_01374 to M.A.M. and PI20_00057 to C.U. P.S.-L. is supported by a ISCIII-CIBERER contract. G.A.-G. was supported by Raregenomics-CM Network (Education Council, Comunidad de Madrid, Spain (B2017/BMD-3721)).