title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
abstract: BACKGROUND
  The heterogeneous group of 3-methylglutaconic aciduria disorders includes several inborn errors of metabolism that affect mitochondrial function through poorly understood mechanisms. We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria. Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation.
  
  
  RESULTS
  Using homozygosity mapping and exome sequencing, we identified a homozygous truncating mutation (p.I562Tfs*23) in CLPB segregating with the disease in this family. CLPB codes for a member of the family of ATPases associated with various cellular activities (AAA(+) proteins) whose function remains unknown. We found that CLPB expression is abolished in fibroblasts from the patients. To investigate the function of this gene, we interfered with the translation of the zebrafish clpb orthologue using an antisense morpholino. The clpb morphants showed an abnormal touch-evoked response with increased swim velocity and tail beat frequency. This motor phenotype is reminiscent of that observed in the patients and is suggestive of increased excitability in neuronal circuits. Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord.
  
  
  CONCLUSIONS
  Altogether, our study suggests that disruption of CLPB causes a novel form of neonatal encephalopathy associated with 3-methylglutaconic aciduria.
authors: CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada.
authors: José-Mario
authors: JM
authors: Capo-Chichi
authors: Department of Neurosciences, Université de Montréal, Montreal, Canada.
authors: Sarah
authors: S
authors: Boissel
authors: Department of Neurosciences, Université de Montréal, Montreal, Canada.
authors: Edna
authors: E
authors: Brustein
authors: CHUM Research Center, Université de Montréal, Montreal, Canada.
authors: Sarah
authors: S
authors: Pickles
authors: Department of Pathology, CHU Sainte-Justine and Université de Montréal, Montréal, Québec.
authors: Catherine
authors: C
authors: Fallet-Bianco
authors: CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada.
authors: Christina
authors: C
authors: Nassif
authors: CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada.
authors: Lysanne
authors: L
authors: Patry
authors: CHUM Research Center, Université de Montréal, Montreal, Canada.
authors: Sylvia
authors: S
authors: Dobrzeniecka
authors: Department of Neurosciences, Université de Montréal, Montreal, Canada CHUM Research Center, Université de Montréal, Montreal, Canada.
authors: Meijiang
authors: M
authors: Liao
authors: CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada Department of Pediatrics, Université de Montréal, Montreal, Canada.
authors: Damian
authors: D
authors: Labuda
authors: CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada Department of Pediatrics, Université de Montréal, Montreal, Canada.
authors: Mark E
authors: ME
authors: Samuels
authors: CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada.
authors: Fadi F
authors: FF
authors: Hamdan
authors: Department of Neurosciences, Université de Montréal, Montreal, Canada CHUM Research Center, Université de Montréal, Montreal, Canada.
authors: Christine
authors: C
authors: Vande Velde
authors: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors: Guy A
authors: GA
authors: Rouleau
authors: Department of Neurosciences, Université de Montréal, Montreal, Canada CHUM Research Center, Université de Montréal, Montreal, Canada.
authors: Pierre
authors: P
authors: Drapeau
authors: CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada Department of Neurosciences, Université de Montréal, Montreal, Canada Department of Pediatrics, Université de Montréal, Montreal, Canada.
authors: Jacques L
authors: JL
authors: Michaud
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D049071:Endopeptidase Clp / Q000235:genetics*; D059472:Exome; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D035781:Siblings; D015027:Zebrafish
chemical_list: D049071:Endopeptidase Clp; C000596639:CLPB protein, human
keywords: 3-methylglutaconic aciduria; CLPB; encephalopathy