A novel mitochondrial SLC25A gene causes CMT and optic atrophy. A. J. Abrams1, M. A. Gonzalez1, A. P. Rebelo1, I. J. Campeanu1, F. G. Speziani1, A. Nemeth2, J. Dallman1, S. Züchner1 1) Hussman Institute for Human Genomics, University of Miami, Miami, FL; 2) Churchill Hospital, Universtiy of Oxford, Oxford, UK.

   Charcot-Marie-Tooth neuropathy (CMT) is one of the most common inherited diseases in neurology. Mutations in MFN2 cause an axonal form of CMT that leads to axon degeneration in the lower limbs and is sometimes accompanied by optic atrophy. Vice versa, patients with dominant optic atrophy, caused by OPA1, can also harbor symptoms of a peripheral neuropathy. MFN2 and OPA1 are both essential factors for mitochondrial fusion suggesting a conserved mechanism involved in the overlapping phenotypes. By exome sequencing families with optic atrophy and CMT, we identified a novel solute carrier gene. Sanger sequencing confirmed that the compound heterozygous changes completely segregate in the pedigree. The gene is conserved in zebrafish and we decided to use the morpholino technology to knock down the SLC25A gene. In great congruence to our patients, morphant fish showed spinal deformities, swimming defects, abnormal motor neuron growth, and appear to be blind. Members of the SLC25 family of mitochondrial solute carrier proteins are predicted to localize to the inner mitochondria membrane and transport a large variety of molecules across the membrane. At least 11 other genetic diseases are caused by mutations in SLC25 genes and all are recessively inherited. This is the first reported case of CMT and optic atrophy to be caused by a mitochondrial carrier gene. Moreover, given the functions of MFN2 and OPA1 and the phenotypic and subcellular overlap, we are currently testing whether SLC25A is a novel, not yet characterized mitochondrial fusion protein. Indeed SLC25A shows significant conservational orthology to ugo1, a yeast mitochondrial fusion gene with no known human orthologue as of today. In summary, with the identification of SLC25A we are expanding the family of mitochondrial membrane proteins involved in optic atrophy and CMT neuropathy and open new opportunities to specifically study these pathways.

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