Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function

Am J Med Genet A. 2016 Jun;170(6):1603-7. doi: 10.1002/ajmg.a.37624. Epub 2016 Mar 17.

Abstract

An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. © 2016 Wiley Periodicals, Inc.

Keywords: DNM1L gene; DRP1; dynamin-related protein 1; mitochondrial disease; mitochondrial dynamics; mitochondrial fission; mitochondrial respiratory chain; pain insensitivity; postnatal microcephaly.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Biomarkers
  • Child, Preschool
  • Exome
  • GTP Phosphohydrolases / genetics*
  • Genetic Association Studies
  • Genotype
  • Heterozygote*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Membrane Potential, Mitochondrial / genetics
  • Microcephaly / diagnosis
  • Microcephaly / genetics*
  • Microtubule-Associated Proteins / genetics*
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Dynamics / genetics*
  • Mitochondrial Proteins / genetics*
  • Mutation*
  • Pain Insensitivity, Congenital / diagnosis
  • Pain Insensitivity, Congenital / genetics*
  • Phenotype

Substances

  • Biomarkers
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • DNM1L protein, human