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

[wolf-hirschhorn syndrome]

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 LETM 1 , 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 LETM 1 expression is associated with some element of mitochondrial dysfunction . Surprisingly , LETM 1 -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 LETM 1 or not , we show , for the first time , that LETM 1 expression is reduced in mitochondria isolated from WHS-patient cells . Furthermore , we show that this is associated with distinct mitochondrial phenotypes , including altered intracellular [Ca (2 +)] 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 LETM 1 expression level ; these phenotypes could underlie and /or contribute to some of the core clinical features of this condition .

Diseases
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Diseases presenting "motor delay and hypotonia are major co-morbidities in whs" symptom

wolf-hirschhorn syndrome

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