A Drosophila mutant of LETM1, a candidate gene for seizures in Wolf-Hirschhorn syndrome.

[wolf-hirschhorn syndrome]

Human Wolf-Hirschhorn syndrome (WHS ) is a multigenic disorder resulting from a hemizygous deletion on chromosome 4 . LETM 1 is the best candidate gene for seizures , the strongest haploinsufficiency phenotype of WHS patients . Here , we identify the Drosophila gene CG 4589 as the ortholog of LETM 1 and name the gene DmLETM 1 . Using RNA interference approaches in both Drosophila melanogaster cultured cells and the adult fly , we have assayed the effects of down-regulating the LETM 1 gene on mitochondrial function . We also show that DmLETM 1 complements growth and mitochondrial K (+)/H (+) exchange (KHE ) activity in yeast deficient for LETM 1 . Genetic studies allowing the conditional inactivation of LETM 1 function in specific tissues demonstrate that the depletion of DmLETM 1 results in roughening of the adult eye , mitochondrial swelling and developmental lethality in third -instar larvae , possibly the result of deregulated mitophagy . Neuronal specific down-regulation of DmLETM 1 results in impairment of locomotor behavior in the fly and reduced synaptic neurotransmitter release . Taken together our results demonstrate the function of DmLETM 1 as a mitochondrial osmoregulator through its KHE activity and uncover a pathophysiological WHS phenotype in the model organism D . melanogaster .

Diseases
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Diseases presenting "the strongest haploinsufficiency phenotype of whs patients" symptom

wolf-hirschhorn syndrome

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