Physical map of the locus associated with generalized LMND, structure of PLEKHG5, and location of the mutation identified in the African family. a, Location and transcriptional direction of the 27 sequenced genes (). b, Structure of PLEKHG5 (). The five isoforms annotated by genome browser are in black, and the two Mammalian Gene Collection Full ORF mRNAs used for plasmid constructions are in gray. The coding exons are shown as vertical bars, illustrating their approximate size and position. The position of the initiation codon (ATG) at nucleotide +1 is indicated in red, and the position of the stop codon (TGA) is indicated in green. The 5′ and 3′ UTRs are shown as shorter vertical bars. Locations of the PH and RhoGEF domains are also shown (). The identified homozygous mutation is located in the PH domain (red arrow). c, Electrophoregram of affected individuals compared with a control, showing the homozygous c.1940 T→C (p.647 Phe→Ser) mutation (GenBank accession number NM_020631.2). WT = wild type. d, Phenylalaline at position 647 (boxed in red) highly conserved across species: Homo sapiens, Pan troglodytes, Mus musculus, Rattus norvegicus, Danio rerio, and Caenorhabditis elegans (). e, Comparison of the PH domain of PLEKHG5 with the PH domain consensus sequence (PH-cons). In this sequence, the eight consensus residues are indicated in capital letters, including the mutant phenylalanine (boxed in red) (). f, Predictive three-dimensional structure of PLEKHG5 (). The RhoGEF domain has an α-helical structure, and the PH domain consists of seven β-sheets, followed by a C-terminal amphipathic helix. The mutation occurs in the area of the β5/β6 loop of the PH domain, which may be part of the phospholipids binding site.