title: A Drosophila mutant of LETM1, a candidate gene for seizures in Wolf-Hirschhorn syndrome.
abstract: Human Wolf-Hirschhorn syndrome (WHS) is a multigenic disorder resulting from a hemizygous deletion on chromosome 4. LETM1 is the best candidate gene for seizures, the strongest haploinsufficiency phenotype of WHS patients. Here, we identify the Drosophila gene CG4589 as the ortholog of LETM1 and name the gene DmLETM1. Using RNA interference approaches in both Drosophila melanogaster cultured cells and the adult fly, we have assayed the effects of down-regulating the LETM1 gene on mitochondrial function. We also show that DmLETM1 complements growth and mitochondrial K(+)/H(+) exchange (KHE) activity in yeast deficient for LETM1. Genetic studies allowing the conditional inactivation of LETM1 function in specific tissues demonstrate that the depletion of DmLETM1 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 DmLETM1 results in impairment of locomotor behavior in the fly and reduced synaptic neurotransmitter release. Taken together our results demonstrate the function of DmLETM1 as a mitochondrial osmoregulator through its KHE activity and uncover a pathophysiological WHS phenotype in the model organism D. melanogaster.
authors.affiliation: Department of Biochemistry, University of Toronto, Canada M5S 1A8. angus.mcquibban@utoronto.ca
authors.forename: Angus G
authors.initials: AG
authors.lastname: McQuibban
authors.forename: Nicholas
authors.initials: N
authors.lastname: Joza
authors.forename: Aram
authors.initials: A
authors.lastname: Megighian
authors.forename: Michele
authors.initials: M
authors.lastname: Scorzeto
authors.forename: Damiano
authors.initials: D
authors.lastname: Zanini
authors.forename: Siegfried
authors.initials: S
authors.lastname: Reipert
authors.forename: Constance
authors.initials: C
authors.lastname: Richter
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Schweyen
authors.forename: Karin
authors.initials: K
authors.lastname: Nowikovsky
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017920:Antiporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000648:ultrastructure; D005123:Eye / Q000473:pathology / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D005816:Genetic Complementation Test; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009420:Nervous System / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D018377:Neurotransmitter Agents / Q000378:metabolism; D009928:Organ Specificity; D034622:RNA Interference; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D012640:Seizures / Q000150:complications* / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D054877:Wolf-Hirschhorn Syndrome / Q000150:complications* / Q000235:genetics*
chemical_list: D017920:Antiporters; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; C544264:Letm1 protein, Drosophila; D024101:Mitochondrial Proteins; D018377:Neurotransmitter Agents