PET100 – Leigh syndrome

Leigh syndrome is a severe, early-onset neurodegenerative disorder marked by bilateral lesions in the brainstem and basal ganglia. Autosomal recessive mutations in genes encoding mitochondrial complex IV assembly factors are a common cause. PET100 encodes a small mitochondrial inner membrane protein essential for cytochrome c oxidase biogenesis and was implicated through genetic and functional studies in individuals with complex IV–deficient Leigh syndrome.

In a cohort of eight affected individuals from six consanguineous Lebanese families, targeted sequencing identified a homozygous c.3G>C (p.Met1Ile) variant abolishing the initiation codon and preventing functional protein expression (PMID:24462369). A haplotype analysis estimated a founder age of >520 years. An additional unrelated British Asian patient presented with fatal neonatal lactic acidosis and isolated complex IV deficiency carrying homozygous c.142C>T (p.Gln48Ter) (PMID:25293719). These nine probands from seven families confirm autosomal recessive inheritance with complete segregation of loss-of-function alleles.

All reported PET100 variants are predicted null alleles (initiation codon or premature stop) and segregate homozygously in affected individuals from multiple families. No disease-causing heterozygous carriers were affected, supporting a recessive mechanism. The variant spectrum is limited to loss-of-function alleles with no conflicting benign reports.

Functional assays in patient fibroblasts showed absent complex IV activity and defective holocomplex assembly. Lentiviral-mediated PET100 expression restored enzyme activity and assembly, confirming causality (PMID:24462369). PET100 localizes to the mitochondrial inner membrane, forming a ~300 kDa subcomplex with complex IV subunits. The p.Gln48Ter protein completely abolishes complex IV assembly in vitro (PMID:25293719).

Mechanistically, biallelic loss of PET100 disrupts cytochrome c oxidase biogenesis, leading to isolated complex IV deficiency, lactic acidosis, seizures, and neurodegeneration. The genetic and experimental concordance across unrelated families and functional rescue support a strong gene–disease association.

Key take-home: Biallelic loss-of-function variants in PET100 are a definitive cause of autosomal recessive Leigh syndrome and should be included in diagnostic panels for complex IV deficiency and early-onset mitochondrial disease.

References

• American Journal of Human Genetics • 2014 • Mutations in PET100 cause complex IV-deficient Leigh syndrome PMID:24462369
• European Journal of Human Genetics • 2015 • A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency PMID:25293719

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