title: The nuclear factor kappaB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset.
abstract: Lower motor neuron diseases (LMNDs) include a large spectrum of clinically and genetically heterogeneous disorders. Studying a large inbred African family, we recently described a novel autosomal recessive LMND variant characterized by childhood onset, generalized muscle involvement, and severe outcome, and we mapped the disease gene to a 3.9-cM interval on chromosome 1p36. We identified a homozygous missense mutation (c.1940 T-->C [p.647 Phe-->Ser]) of the Pleckstrin homology domain-containing, family G member 5 gene, PLEKHG5. In transiently transfected HEK293 and MCF10A cell lines, we found that wild-type PLEKHG5 activated the nuclear factor kappa B (NF kappa B) signaling pathway and that both the stability and the intracellular location of mutant PLEKHG5 protein were altered, severely impairing the NF kappa B transduction pathway. Moreover, aggregates were observed in transiently transfected NSC34 murine motor neurons overexpressing the mutant PLEKHG5 protein. Both loss of PLEKHG5 function and aggregate formation may contribute to neurotoxicity in this novel form of LMND.
authors.affiliation: Centre de Génétique Humaine et Unité de Génétique Médicale, Université Catholique de Louvain, Brussels, Belgium. isabelle.maystadt@ipg.be
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.forename: René
authors.initials: R
authors.lastname: Rezsöhazy
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.forename: Sandra
authors.initials: S
authors.lastname: Duque
authors.forename: Pascal
authors.initials: P
authors.lastname: Vannuffel
authors.forename: Sophie
authors.initials: S
authors.lastname: Remacle
authors.forename: Barbara
authors.initials: B
authors.lastname: Lambert
authors.forename: Mustapha
authors.initials: M
authors.lastname: Najimi
authors.forename: Etienne
authors.initials: E
authors.lastname: Sokal
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Louis
authors.initials: L
authors.lastname: Viollet
authors.forename: Christine
authors.initials: C
authors.lastname: Verellen-Dumoulin
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D005808:Genes, Recessive; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000235:genetics*; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism*; D010375:Pedigree; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D012694:Serine / Q000737:chemistry / Q000235:genetics; D014162:Transfection
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; C522397:PLEKHG5 protein, human; D012694:Serine; D010649:Phenylalanine