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

congenital toxoplasmosis

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dentin dysplasia

dentinogenesis imperfecta

dracunculiasis

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

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esophageal squamous cell carcinoma

fabry disease

familial mediterranean fever

gm1 gangliosidosis

harlequin ichthyosis

heparin-induced thrombocytopenia

hirschsprung disease

hodgkin lymphoma, classical

holt-oram syndrome

hydrocephalus with stenosis of the aqueduct of sylvius

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

malignant atrophic papulosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

omenn syndrome

oral submucous fibrosis

papillon-lefÃ¨vre syndrome

pendred syndrome

phenylketonuria

primary effusion lymphoma

primary hyperoxaluria type 1

severe combined immunodeficiency

sneddon syndrome

triple a syndrome

trochlear dysplasia

von hippel-lindau disease

waldenstrÃ¶m macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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