The p.Leu870Ser MCM3AP mutation in a Lebanese family localizes to the Sac3 domain of GANP. (A) The pedigree shows segregation of the mutation that has been confirmed by (B) Sanger sequencing analysis traces. Circles denote females and squares denote males. The asterisk denotes the nucleotide position at which a homozygous T to C transition is observed in all affected siblings and both parents are heterozygous for the T to C transition. A sequence trace of a neurologically normal unrelated individual shows a homozygous T allele. (C) Alignment analysis for the p.Leu870Ser mutation for MCM3AP orthologues in different species. Amino acid position 870 is boxed in red. (D) GANP protein showing the different domains and location of mutations for recessive CMT. Previously reported mutations (below) and the novel mutation in this study (above) are shown. (E) Structure of the TREX2 complex including the GANP protein, showing CMT causing mutations within the Sac3 domain. Diagram was drawn using the crystal structure of the S. cerevisiae homologue (PDB: 3t5v) (Ellisdon et al., 2012). Sac3 residues are shown in blue, in complex with Thp1 (human homologue PCID2) in red and Sem1 (human homologue DSS1) in yellow. CMT mutations are shown as grey sticks and the newly identified p.Leu870Ser mutation in orange. Box area is enlarged to show CMT mutations enriched around the Sac3/Thp1 interaction interface (Sac3 interacting residues highlighted in green).