A Founder Mutation in PET100 Causes Isolated Complex IV Deficiency in Lebanese Individuals with Leigh Syndrome

Abstract

Leigh syndrome (LS) is a severe neurodegenerative disorder with characteristic bilateral lesions, typically in the brainstem and basal ganglia. It usually presents in infancy and is genetically heterogeneous, but most individuals with mitochondrial complex IV (or cytochrome c oxidase) deficiency have mutations in the biogenesis factor SURF1. We studied eight complex IV-deficient LS individuals from six families of Lebanese origin. They differed from individuals with SURF1 mutations in having seizures as a prominent feature. Complementation analysis suggested they had mutation(s) in the same gene but targeted massively parallel sequencing (MPS) of 1,034 genes encoding known mitochondrial proteins failed to identify a likely candidate. Linkage and haplotype analyses mapped the location of the gene to chromosome 19 and targeted MPS of the linkage region identified a homozygous c.3G>C (p.Met1?) mutation in C19orf79. Abolishing the initiation codon could potentially still allow initiation at a downstream methionine residue but we showed that this would not result in a functional protein. We confirmed that mutation of this gene was causative by lentiviral-mediated phenotypic correction. C19orf79 was recently renamed PET100 and predicted to encode a complex IV biogenesis factor. We showed that it is located in the mitochondrial inner membrane and forms a ∼300 kDa subcomplex with complex IV subunits. Previous proteomic analyses of mitochondria had overlooked PET100 because its small size was below the cutoff for annotating bona fide proteins. The mutation was estimated to have arisen at least 520 years ago, explaining how the families could have different religions and different geographic origins within Lebanon.

Human mitochondrial COX1 assembly into cytochrome c oxidase at a glance

“…A similar phenotype is observed in patients with mutations in the PET100 gene (Lim et al, 2014;Oláhová et al, 2014). PET100 is present in a 300 kDa complex together with other subunits of the COX (Lim et al, 2014). However, the function of PET100 is still elusive.…”

“…A mutation in the C2orf64-encoding gene (COA5) leads to an accumulation of various COX assembly intermediates and reduced steady-state levels of COX1, thus explaining the complex IV deficiency (Huigsloot et al, 2011). A similar phenotype is observed in patients with mutations in the PET100 gene (Lim et al, 2014;Oláhová et al, 2014). PET100 is present in a 300 kDa complex together with other subunits of the COX (Lim et al, 2014).…”

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…First identified in 1977 [86], CIV deficiencies (OMIM # 220110) can present as myopathies, facial dimorphism and lactic acidosis [86,87]. The majority of known pathogenic mutations are in nDNA genes that encode CIV structural subunits or assembly factors [60], including COX6B1 [88], and PET100 [89] (Table 1).…”

Use of Exome Sequencing in Inborn Error of Metabolism: A Systematic Review

“…Many studies using conventional genotyping methods, such as PCR-RFLP, Massively Parallel Sequencing (MSP), single specific primer-PCR and direct sequencing reported mtND2 to mtND6 as the most frequent mutation associated with Leigh syndrome. These techniques also helped to identify other mutations such as SLC19A3 (Vernau et al, 2013), C19orf79 (Lim et al, 2014), NDUFS1 (Tuppen et al, 2010), SURF1 (Hurrell et al, 2007), SUCLA2 (Vernau et al, 2013) and MT-ATP6 (Manfredi et al, 2002) hence, sometimes failed in the detection of functional mutations (Lee et al, 2001). Moreover, mutation in GYG2, MT-ATP6 and SLC19A3 genes has been reported in association with ES.…”