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 .

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achondroplasia

acute rheumatic fever

adrenal incidentaloma

adrenomyeloneuropathy

alpha-thalassemia

aniridia

aromatase deficiency

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

classical phenylketonuria

congenital adrenal hyperplasia

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cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

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dracunculiasis

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epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

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fabry disease

familial mediterranean fever

gm1 gangliosidosis

harlequin ichthyosis

heparin-induced thrombocytopenia

hirschsprung disease

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junctional epidermolysis bullosa

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primary hyperoxaluria type 1

severe combined immunodeficiency

sneddon syndrome

triple a syndrome

trochlear dysplasia

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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