The nuclear factor kappaB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset.
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.
Maystadt
Isabelle
I
Centre de Génétique Humaine et Unité de Génétique Médicale, Université Catholique de Louvain, Brussels, Belgium. isabelle.maystadt@ipg.be
Rezsöhazy
René
R
Barkats
Martine
M
Duque
Sandra
S
Vannuffel
Pascal
P
Remacle
Sophie
S
Lambert
Barbara
B
Najimi
Mustapha
M
Sokal
Etienne
E
Munnich
Arnold
A
Viollet
Louis
L
Verellen-Dumoulin
Christine
C
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
D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; C522397:PLEKHG5 protein, human; D012694:Serine; D010649:Phenylalanine