NDUFS8 – NDUFS8-related Leigh syndrome

The nuclear-encoded NDUFS8 subunit of mitochondrial complex I was first implicated in Leigh syndrome by Loeffen et al. following compound heterozygous missense substitutions c.236C>T (p.Pro79Leu) and c.305G>A (p.Arg102His) in a patient with neuro­pathologically confirmed disease (PMID:9837812). This finding established autosomal recessive inheritance and a pathogenic mechanism involving defective iron–sulfur cluster incorporation.

Subsequent case series identified biallelic NDUFS8 variants in diverse populations. A late-onset Leigh syndrome case harbored compound heterozygous c.254C>T (p.Pro85Leu) and c.413G>A (p.Arg138His) alleles with reduced NDUFS8 levels and secondary complex I destabilization (PMID:15159508). A consanguineous family exhibited three siblings with either homozygous or compound heterozygous c.160C>T (p.Arg54Trp) and c.161G>A (p.Arg54Gln), expanding the phenotype to “PEO plus” Leigh syndrome (PMID:23430795).

An Iranian girl presented with infantile Leigh syndrome with a homozygous c.484G>A (p.Val162Met) variant, confirming recurrent autosomal recessive mutations in NDUFS8 (PMID:37180333).

Broad exome sequencing of complex I deficiency cohorts further defined a spectrum of NDUFS8 lesions, including rare missense alleles c.476C>A (p.Ala159Asp), c.187G>C (p.Glu63Gln), and c.229C>T (p.Arg77Trp) in unrelated patients; each variant was validated by wild-type cDNA rescue of complex I activity in patient fibroblasts (PMID:22499348).

Collectively, at least 8 probands across 5 families carry biallelic NDUFS8 variants, including multiple missense substitutions and one frameshift, with 2 affected siblings demonstrating segregation ([PMID:9837812]; [PMID:15159508]; [PMID:23430795]; [PMID:37180333]; [PMID:22499348]). Autosomal recessive inheritance is confirmed by parental carrier status in all reports.

Functional assays in the obligate aerobic yeast Yarrowia lipolytica recapitulate the P79L and R102H defects with ~50% residual complex I activity (PMID:11004438), and patient fibroblast rescue experiments with wild-type NDUFS8 restore enzyme assembly and NADH oxidation rates (PMID:22499348).

The preponderance of loss-of-function and destabilizing missense mutations, along with consistent genetic segregation and biochemical data, supports a haploinsufficiency mechanism leading to defective iron–sulfur cluster binding and complex I assembly. No conflicting evidence has been reported.

In conclusion, robust genetic, segregation, and functional evidence classify the NDUFS8–Leigh syndrome association as Strong. Comprehensive NDUFS8 sequencing should be incorporated into diagnostic panels for Leigh syndrome, as identification of biallelic variants informs prognosis and genetic counseling.

References

• American Journal of Human Genetics • 1998 • The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. PMID:9837812
• Neurology • 2004 • Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations. PMID:15159508
• JIMD Reports • 2013 • NDUFS8-related Complex I Deficiency Extends Phenotype from "PEO Plus" to Leigh Syndrome. PMID:23430795
• Clinical Case Reports • 2023 • Molecular analysis of gene variants in an Iranian family with psychomotor retardation mitochondrial disorder patient. PMID:37180333
• Journal of Medical Genetics • 2012 • Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. PMID:22499348
• Biochimica et Biophysica Acta • 2000 • Application of the obligate aerobic yeast Yarrowia lipolytica as a eucaryotic model to analyse Leigh syndrome mutations in the complex I core subunits PSST and TYKY. PMID:11004438

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