LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition

Hart, LesleyRuth, Rauch, Anita, Carr, Antony, Vermeesch, Joris R and O'Driscoll, Mark (2014) LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition. Disease Models and Mechanisms, 7. pp. 535-545. ISSN 1754-8403

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution.

Download (966kB) | Preview

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, 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.

Item Type: Article
Keywords: LETM1, Wolf-Hirschhorn syndrome, Mitochondria
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Gee Wheatley
Date Deposited: 07 May 2014 07:39
Last Modified: 07 Mar 2017 12:26
URI: http://sro.sussex.ac.uk/id/eprint/48413

View download statistics for this item

📧 Request an update