Disease Models and Mechanisms vol:7 issue:5 pages:535-545
AbstractWolf-Hirschhorn syndrome (WHS) represents an archetypical example of a contiguous gene deletion disorder; a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are significant co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes an mitochondrial inner membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism; principally for seizures but also for other core features of WHS including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from WHS patients. Here, using a unique panel of WHS patient-derived cell lines with differing sized deletions incorporating LETM1 or not, we show for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS patient cells. Further, we show that this is associated with distinct mitochondrial phenotypes including altered intracellular [Ca(2+)] levels, dysfunctional mitochondrial transition pore opening along with hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression levels; phenotypes which may underlie and/or contribute to some of the core clinical features of this condition.