LETM1_and_WHS__Dis__Model__Mech_-2014-Hart-535-45.pdf (943.62 kB)
LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition
journal contribution
posted on 2023-06-08, 17:11 authored by LesleyRuth Hart, Anita Rauch, Antony CarrAntony Carr, Joris R Vermeesch, Mark O'DriscollMark O'DriscollWolf-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, hyperpolarizationand superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHScohort. Our findings identify novel cellular phenotypes in WHSattributable to a 50% reduction in LETM1 expression level; thesephenotypes could underlie and/or contribute to some of the core clinical features of this condition.
History
Publication status
- Published
File Version
- Published version
Journal
Disease Models and MechanismsISSN
1754-8403Publisher
Company of BiologistsExternal DOI
Volume
7Page range
535-545Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2014-05-07First Open Access (FOA) Date
2014-05-07First Compliant Deposit (FCD) Date
2014-05-06Usage metrics
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