Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships

The most frequent cause of isolated complex III deficits is mutations to the nuclear‐encoded ATPase BCS1L. Disease phenotypes are varied and can be as mild as Björnstad syndrome, characterized by pili torti and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L mutations are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving low birth weight, renal and hepatic pathologies, hypotonia, and developmental delays. We analyzed all published patient cases of mutations to BCS1L and modeled the tertiary and quaternary structure of the BCS1L protein to map the location of disease‐causing BCS1L mutations. We show that higher order structural analysis can be used to understand the phenotype observed in a patient with the novel compound heterozygous c.550C>T(p.Arg184Cys) and c.838C>T(p.Leu280Phe) mutations. More broadly, higher order structural analysis reveals genotype–phenotype relationships within the intermediate complex III deficiency category that help to make sense of the spectrum of observed phenotypes. We propose a change in nomenclature that unifies the intermediate phenotype under “BCS1L Mitopathies”. Patterns in genotype–phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L.