The Lebanese Allele in the PET100 Gene: Report on Two New Families with Cytochrome c Oxidase Deficiency

Abstract

Cytochrome c oxidase deficiency is caused by mutations in any of at least 30 mitochondrial and nuclear genes involved in mitochondrial complex IV biogenesis and structure, including the recently identified PET100 gene. Here, we report two families, of which one is consanguineous, with two affected siblings each. In one family, the siblings presented with developmental delay, seizures, lactic acidosis, abnormal brain magnetic resonance imaging, and low muscle mitochondrial complex IV activity at 30%. In the other family, the two siblings, now deceased, had a history of global developmental delay, failure to thrive, muscular hypotonia, seizures, developmental regression, respiratory insufficiency, and lactic acidosis. By whole exome sequencing, a missense mutation in exon 1 of the PET100 gene (c.3G > C; [p.Met1?]) was identified in both families. A review of the clinical description and literature is discussed, highlighting the importance of this variant in the Lebanese population.

Mitochondrial disorders of the OXPHOS system

“…COX20 is involved in the stabilization of MT-CO2 early after its PET100 and PET117 are the human homologs of two S. cerevisiae assembly factors involved in the intermediate steps of cIV assembly, stabilizing the MT-CO2 module [186]. A particular pathological variant in PET100 affecting the starting codon was identified as the cause of Leigh Syndrome in a group of patients of Lebanese origin [232,233]. In addition, a different PET100 truncating mutation was determined as the cause of cIV deficiency and fatal infantile lactic acidosis [234].…”

Functions of Cytochrome c Oxidase Assembly Factors

“…COA7 mutants result in COX deficiency causing leukoencephalopathies and peripheral neuropathies [ 82 , 83 ] and this deficiency can be restored by inhibiting cytosolic degradation of COA7 indicating these mutations delay COA7 import into mitochondria which are still capable of contributing to COX assembly [ 84 ]. Mutations in PET100 also cause COX deficiency through a truncation and an import defect [ 85 , 86 , 87 ]. PET117 mutations cause COX deficiency, most likely through its role in assisting haem synthesis coupling to association into Cox1 [ 88 ].…”

Catalogue for Transmission Genetics in Arabs (CTGA) Database: Analysing Lebanese Data on Genetic Disorders

“…One such example is the p.Met1Ile mutation (rs587777839) in PET100. The latter has been identified in over 31 subjects exclusively from 12 different Lebanese families to date [30][31][32][33]. Another variant to note is the well-known p.Cys681X variant in the LDLR gene (rs121908031).…”