NDUFB11 – Mitochondrial Disease

NDUFB11 encodes an accessory subunit of mitochondrial respiratory chain complex I, essential for assembly and function of NADH:ubiquinone oxidoreductase. Variants in NDUFB11 have been identified in patients presenting with a spectrum of mitochondrial disease (MD) manifestations, including lactic acidosis, cardiomyopathy, and complex I deficiency, consistent with the broad phenotypic heterogeneity of MONDO:0044970 (NDUFB11; mitochondrial disease).

Genetic Evidence

NDUFB11-related MD follows an X-linked inheritance pattern, with hemizygous or de novo nonsense and missense variants identified in 10 unrelated probands across five studies. One patient with an NDUFB11 variant was diagnosed by WES in an Estonian MD cohort ([PMID:30009132]). A de novo nonsense variant c.262C>T (p.Arg88Ter) was reported in a female with histiocytoid cardiomyopathy and overlaps with a case of microphthalmia with linear skin defects ([PMID:28050600]). Two male patients harbored de novo hemizygous missense variants c.286T>C (p.Ser96Pro) and c.361G>A (p.Glu121Lys) presenting lactic acidosis and hypertrophic cardiomyopathy ([PMID:30423443]), one neonatal lethal case carried c.338G>A (p.Arg113Lys) affecting splicing ([PMID:36675256]), and a recurring in‐frame deletion c.276_278del (p.Phe93del) was observed in five males with sideroblastic anemia and complex I instability ([PMID:27488349]). No segregation data are available.

Variant Spectrum

Reported pathogenic variants include nonsense (n = 2), missense (n = 4), in-frame deletion (n = 1), and splice-altering substitutions (n = 1). Recurrent p.Phe93del was seen in a founder cohort of X-linked sideroblastic anemia. The c.262C>T (p.Arg88Ter) truncating allele has been observed in two unrelated cases, indicating recurrence at CpG dinucleotides.

Functional Evidence

Patient-derived fibroblasts and muscle biopsies show reduced NDUFB11 protein levels, impaired complex I assembly, and decreased NADH:ubiquinone oxidoreductase activity. Lentiviral complementation with wild-type NDUFB11 restores complex I function ([PMID:30423443]). Splicing assays confirmed that c.338G>A disrupts canonical transcript expression and leads to a nonfunctional alternative isoform ([PMID:36675256]). The p.Phe93del allele induces complex I instability and reduced activity in K562 cells, recapitulating mitochondrial respiratory defects ([PMID:27488349]).

Mechanism & Clinical Integration

Collectively, the data support a loss-of-function mechanism via impaired complex I assembly. The consistent biochemical signature across multiple variant classes and rescue by complementation underpin the pathogenic role of NDUFB11 in mitochondrial disease. NDUFB11 should be included in MD gene panels, and WES/WGS can effectively detect both coding and splice-site variants.

Key Take-home: Hemizygous and de novo NDUFB11 loss-of-function variants cause X-linked mitochondrial disease with complex I deficiency, guiding diagnosis by sequencing and functional assays.

References

• Molecular genetics and metabolism reports • 2018 • Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia. PMID:30009132
• Cold Spring Harbor molecular case studies • 2017 • Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11. PMID:28050600
• European journal of medical genetics • 2019 • Diverse phenotype in patients with complex I deficiency due to mutations in NDUFB11. PMID:30423443
• International journal of molecular sciences • 2023 • A Novel Mutation Associated with Neonatal Lethal Cardiomyopathy Leads to an Alternative Transcript Expression in the X-Linked Complex I NDUFB11 Gene. PMID:36675256
• Blood • 2016 • A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia. PMID:27488349

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