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
Validation

Diseases presenting "intellectual disability" symptom

22q11.2 deletion syndrome

alexander disease

alpha-thalassemia

aniridia

child syndrome

cohen syndrome

cowden syndrome

hirschsprung disease

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

monosomy 21

oculocutaneous albinism

oligodontia

phenylketonuria

proteus syndrome

triple a syndrome

wolf-hirschhorn syndrome

This symptom has already been validated