Abstract
Wolf-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 major co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes a 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 individuals with WHS. Here, using a unique panel of WHS-patient-derived cell lines with deletions of differing sizes, incorporating LETM1 or not, we show, for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS-patient cells. Furthermore, we show that this is associated with distinct mitochondrial phenotypes, including altered intracellular [Ca2+] levels, dysfunctional mitochondrial transition-pore opening, 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 level; these phenotypes could underlie and/or contribute to some of the core clinical features of this condition.
Highlights
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion disorder caused by hemizygous deletion within chromosome 4p16.3 (Bergemann et al, 2005; Hirschhorn, 2008)
In this study, the authors use a unique panel of cell lines derived from individuals with WHS to show that leucine-zipper EF-hand-containing transmembrane protein 1 (LETM1) expression is reduced in cell extracts and mitochondria isolated from those with LETM1 haploinsufficiency
Implications and future directions These findings provide the first direct evidence that cells with LETM1 haploinsufficiency obtained from individuals with WHS exhibit reduced LETM1 expression and that mitochondrial dysfunction is a consequence of the 50% reduction in LETM1 expression, thereby providing new pathomechanistic insights into WHS
Summary
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion disorder caused by hemizygous deletion within chromosome 4p16.3 (Bergemann et al, 2005; Hirschhorn, 2008). The core clinical features of WHS consist of microcephaly, growth retardation, intellectual disability, atrial and ventricular septal defects, skeletal. WHS is generally regarded as a multigenic disorder, two critical regions have been described: WHSCR1 and WHSCR2, for WHS critical region 1 and 2, respectively (see Fig. 1) These critical regions are based on the demarcation of the minimum region of overlap in individuals exhibiting WHS-like phenotypes. It is thought that haploinsufficiency of WHSC1 and WHSC2 accounts for many of the core phenotypes in WHS
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