title: Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia.
abstract: Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.
authors.affiliation: Department of Neurology, University of California, Los Angeles, CA, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
authors.forename: Janos
authors.initials: J
authors.lastname: Steffen
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Yourshaw
authors.affiliation: Department of Neurology, University of California, Los Angeles, CA, USA.
authors.forename: Hafsa
authors.initials: H
authors.lastname: Mamsa
authors.affiliation: Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Erik
authors.initials: E
authors.lastname: Andersen
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.affiliation: Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Pope
authors.affiliation: Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Howell
authors.affiliation: Anatomical Pathology, The Alfred Hospital; Howard Florey Neuroscience Institute, Melbourne, Victoria, Australia.
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.affiliation: Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kornberg
authors.affiliation: Department of Neonatology, Bürgerhospital Frankfurt am Main, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Joseph
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.affiliation: Institut für Humangenetik der RWTH Aachen, Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.affiliation: Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, CA, USA.|Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Koehler
authors.affiliation: Department of Neurology, University of California, Los Angeles, CA, USA.|Department of Neurobiology, University of California, Los Angeles, CA, USA.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Jen
mesh_terms: D000596:Amino Acids / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000002:abnormalities; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002526:Cerebellar Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D015331:Cohort Studies; D004625:Embryo, Nonmammalian; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D028061:Phosphate Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015027:Zebrafish
chemical_list: D000596:Amino Acids; D024101:Mitochondrial Proteins; D028061:Phosphate Transport Proteins; C584459:SLC25A46 protein, human
keywords: SLC25A46; mitochondria; optic atrophy spectrum disorder; pontocerebellar hypoplasia