A MOLECULAR EXPLANATION OF SLC25A1 DEFICIENCY RESULTING IN AGENESIS OF CORPUS CALLOSUM AND OPTIC NERVE HYPOPLASIA

Mitochondrial carriers (MCs) form a large family of nuclear-encoded transporters embedded in the inner mitochondrial membrane and in a few cases in other organelle membranes (Palmieri, 2013). The members of this superfamily are widespread in eukaryotes and involved in numerous metabolic pathways and cell functions. They can be easily recognized by their striking sequence features, i.e., a tripartite structure, six transmembrane α-helices and a 3-fold repeated signature motifs. Members of the family vary greatly in the nature and size of their transported substrates, modes of transport (i.e., uniport, symport or antiport) and driving forces, although the molecular mechanism of substrate translocation may be basically the same. In recent years mutations in the MC genes have been shown to be responsible for 11 diseases (Palmieri, 2013), highlighting the important role of MCs in metabolism. MC impairing mutations affect three main regions crucial for substrate translocation. A first group of mutations affects MC conformational changes and locates at PG levels or at the aromatic belts (Pierri et al., 2013). A second group of mutations affects substrate specificity and locates at the common substrate binding site (Robinson et al., 2008) and at the substrate binding area (Pierri et al., 2013). A further group of mutations locate at residues of the m-/c-gates (Palmieri et al., 2013; Robinson et al., 2008) and at residues of the m-gate area (Pierri et al. 2013). For this last group of mutations, it appears difficult to establish if the impaired function is due to the lack of substrate specificity (or substrate recognition) or to the wrong triggering of conformational changes. Two mutations, one at the PG level 1 and one at the common substrate binding site, impairing citrate translocation within SLC25A1_CTP protein are presented. The two mutations are found to be responsible of agenesis of corpus callosum and optic nerve hypoplasia (Edvardson et al., 2013). References 1. Palmieri F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Aspects Med. 2013;34:465. 2. Pierri CL, Palmieri F, De Grassi A. Single-nucleotide evolution quantifies the importance of each site along the structure of mitochondrial carriers. Cell Mol Life Sci. 2013. 3. Robinson AJ, Overy C, Kunji ER. The mechanism of transport by mitochondrial carriers based on analysis of symmetry. Proc Natl Acad Sci U S A. 2008;105:17766. 4. Edvardson S, Porcelli V, Jalas C, Soiferman D, Kellner Y, Shaag A, Korman SH, Pierri CL, Scarcia P, Fraenkel ND, Segel R, Schechter A, Frumkin A, Pines O, Saada A, Palmieri L, Elpeleg O. Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter. J Med Genet. 2013;50:240.