SURF1 – Leigh syndrome

Association and Phenotype

SURF1 encodes a mitochondrial inner membrane protein essential for cytochrome c oxidase (COX) assembly. Biallelic pathogenic variants in SURF1 cause autosomal recessive Leigh syndrome, characterized by early infancy onset of psychomotor regression, hypotonia, ataxia, peripheral neuropathy, and lactic acidosis. Neuroimaging reveals symmetrical bilateral lesions in basal ganglia, brainstem, and cerebellum, with occasional spinal nerve root enhancement on MRI ([PMID:9843204]). Peripheral neuropathy and demyelinating features are frequent, underscoring the multisystemic mitochondrial involvement.

Genetic Evidence

More than 300 unrelated probands have been reported with SURF1‐related Leigh syndrome, harboring predominantly loss‐of‐function variants including frameshift, nonsense, and splice‐site mutations, and fewer missense alleles ([PMID:22488715], [PMID:23829769]). The prototypical recurrent Polish founder allele c.845_846delCT accounts for ~78% of SURF1 alleles in Eastern Europe ([PMID:18583168]). Compound heterozygotes and homozygotes for splice‐junction (e.g., c.240+1G>T) and exon deletion variants underscore autosomal recessive inheritance and a consistent variant spectrum.

Segregation and Family Studies

Segregation of SURF1 variants with Leigh syndrome has been confirmed in over 50 families, including consanguineous pedigrees and uniparental disomy cases; for example, paternal isodisomy of chromosome 9 leading to homozygosity for c.241-1G>C ([PMID:31454184]). These data support a robust Mendelian recessive inheritance pattern with high penetrance.

Functional and Experimental Evidence

Patient fibroblasts lack mature Surf1 protein and exhibit markedly reduced COX subunit levels, demonstrating a failure of complex IV assembly ([PMID:10556303]). Surf1 knockout mice show >90% embryonic lethality, profound COX deficiency in muscle and liver, and muscle weakness, recapitulating key aspects of human Leigh syndrome ([PMID:12566387]). Hypoxic and hypercapnic challenges in Surf1−/− models reveal impaired respiratory control ([PMID:21167962]).

Mechanism and Modifiers

Loss of SURF1 disrupts COX biogenesis, leading to impaired oxidative phosphorylation and neurodegeneration. Missense alleles (e.g., c.821A>G; p.Tyr274Cys) can result in milder courses with delayed onset and longer survival, indicating genotype–phenotype correlations ([PMID:19780766]). Upregulation of mitochondrial stress responses and partial rescue by transcriptional activators in model systems highlight potential therapeutic targets.

Summary and Clinical Utility

The association between SURF1 and Leigh syndrome is Definitive based on extensive clinical reports, segregation, and concordant functional studies over >15 years. Genetic testing for SURF1 variants is recommended in infants with COX‐deficient Leigh phenotype, and COX activity assays in noninvasive samples (buccal cells) can facilitate rapid screening.

Take-Home Message

Biallelic SURF1 loss‐of‐function variants cause a clinically and genetically homogeneous form of Leigh syndrome with robust functional validation, making SURF1 testing a cornerstone of mitochondrial disorder diagnostics.

References

• Nature Genetics • 1998 • SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. [PMID:9843204]
• Human Mutation • 2012 • SURF1-associated Leigh syndrome: a case series and novel mutations. [PMID:22488715]
• Orphanet Journal of Rare Diseases • 2013 • SURF1 deficiency: a multi-centre natural history study. [PMID:23829769]
• Human Molecular Genetics • 1999 • Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome c oxidase deficiency. [PMID:10556303]
• Human Molecular Genetics • 2003 • Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice. [PMID:12566387]
• Clinical Genetics • 2009 • SURF1 missense mutations promote a mild Leigh phenotype. [PMID:19780766]

Evidence Based Scoring (AI generated)

Gene–Disease Association Definitive Over 300 unrelated probands with biallelic loss-of-function variants; consistent autosomal recessive inheritance and robust functional validation Genetic Evidence Strong More than 300 probands across multiple cohorts with frameshift, nonsense, and splice variants; recurrent c.845_846delCT founder allele ([PMID:22488715], [PMID:18583168]) Functional Evidence Moderate Surf1 knockout mice recapitulate COX deficiency and embryonic lethality ([PMID:12566387]); patient cells lack Surf1 and fail COX assembly ([PMID:10556303])