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Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria

José-Mario Capo-Chichi1, Sarah Boissel2, Edna Brustein2

  • 1CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada.

Journal of Medical Genetics
|February 5, 2015
PubMed

Insights

A novel mutation in the CLPB gene causes a severe neonatal encephalopathy with 3-methylglutaconic aciduria. This genetic disorder affects mitochondrial function and neuronal excitability, leading to significant neurological impairment in affected infants.

Area of Science:

  • Biochemistry
  • Genetics
  • Neuroscience

Background:

  • 3-methylglutaconic aciduria disorders are a group of inborn errors of metabolism impacting mitochondrial function.
  • Four siblings from a consanguineous family presented with microcephaly, low birth weight, severe encephalopathy, and 3-methylglutaconic aciduria.
  • Neurological examination revealed severe hypertonia and prolonged clonic movements upon tactile stimulation.

Purpose of the Study:

  • To identify the genetic cause of a novel form of neonatal encephalopathy associated with 3-methylglutaconic aciduria.
  • To investigate the function of the identified gene, CLPB, in cellular and organismal models.

Main Methods:

  • Homozygosity mapping and exome sequencing were used to identify the causative mutation.
  • CLPB gene expression was analyzed in patient fibroblasts.
  • Zebrafish clpb orthologue translation was inhibited using antisense morpholinos to study functional consequences.

Main Results:

  • A homozygous truncating mutation (p.I562Tfs*23) in the CLPB gene was identified in the affected family.
  • CLPB expression was abolished in patient fibroblasts.
  • Zebrafish morphants exhibited motor abnormalities, including increased swim velocity and tail beat frequency, suggesting increased neuronal excitability.
  • Knockdown of clpb in zebrafish led to altered numbers of inhibitory glycinergic and excitatory glutamatergic neurons in the spinal cord.

Conclusions:

  • Disruption of the CLPB gene causes a novel form of neonatal encephalopathy.
  • The study implicates CLPB in the regulation of neuronal excitability and interneuron development.
  • This finding expands the spectrum of 3-methylglutaconic aciduria disorders and their underlying genetic causes.
Abstract

Keywords:
3-methylglutaconic aciduriaCLPBencephalopathy

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