TMEM126B was first identified through its interaction with the mitochondrial complex I assembly factor (MCIA) complex through a proteomic profiling strategy. Complexome profiling demonstrated that TMEM126B acts with other MCIA proteins (Ecsit, ACAD9, NDUFAF1, TIMMDC1) to append the preformed Q module to the membrane bound P module during the assembly of complex I. There are three reports of TMEM126B-related pathology in the literature to date, describing ten affected individuals from eight families; the initial cases were reported concurrently in the American Journal of Human Genetics in 2016. Sanchez-Caballero et al. (2016) describe three unrelated cases whilst Alston et al. (2016) describe six patients from four families; more recently a singleton case has been presented in Theunissen et al.(2017). Whilst the clinical features associated with genetic defects involving other complex I assembly factors have wide phenotypic heterogeneity (including neonatal lactic acidosis, cardiomyopathy and Leigh syndrome), the patients who were found to harbor pathogenic TMEM126B variants shared a similar case history, with early-onset (age range 2m-15y) persisting myopathy and exercise intolerance as their predominant clinical features. All affected individuals were found to harbor recessive variants and interestingly only four variant alleles were responsible, detected in multiple, seemingly unrelated families that likely represent founder variants. TMEM126B-related mitochondrial disease is a rare disorder, as far as we are aware, these are the only cases identified to date.
TMEM126B