CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease

Am J Hum Genet. 2015 Jan 8;96(1):121-35. doi: 10.1016/j.ajhg.2014.12.003.


CODAS syndrome is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. Using whole-exome and Sanger sequencing, we identified four LONP1 mutations inherited as homozygous or compound-heterozygous combinations among ten individuals with CODAS syndrome. The individuals come from three different ancestral backgrounds (Amish-Swiss from United States, n = 8; Mennonite-German from Canada, n = 1; mixed European from Canada, n = 1). LONP1 encodes Lon protease, a homohexameric enzyme that mediates protein quality control, respiratory-complex assembly, gene expression, and stress responses in mitochondria. All four pathogenic amino acid substitutions cluster within the AAA(+) domain at residues near the ATP-binding pocket. In biochemical assays, pathogenic Lon proteins show substrate-specific defects in ATP-dependent proteolysis. When expressed recombinantly in cells, all altered Lon proteins localize to mitochondria. The Old Order Amish Lon variant (LONP1 c.2161C>G[p.Arg721Gly]) homo-oligomerizes poorly in vitro. Lymphoblastoid cell lines generated from affected children have (1) swollen mitochondria with electron-dense inclusions and abnormal inner-membrane morphology; (2) aggregated MT-CO2, the mtDNA-encoded subunit II of cytochrome c oxidase; and (3) reduced spare respiratory capacity, leading to impaired mitochondrial proteostasis and function. CODAS syndrome is a distinct, autosomal-recessive, developmental disorder associated with dysfunction of the mitochondrial Lon protease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP-Dependent Proteases / genetics*
  • ATP-Dependent Proteases / metabolism
  • Adolescent
  • Animals
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Craniofacial Abnormalities / genetics*
  • DNA Copy Number Variations
  • DNA, Mitochondrial / genetics
  • Exome
  • Eye Abnormalities / genetics*
  • Female
  • Gene Frequency
  • Growth Disorders / genetics*
  • HEK293 Cells
  • HeLa Cells
  • Hip Dislocation, Congenital / genetics*
  • Homozygote
  • Humans
  • Infant
  • Male
  • Mice
  • Microscopy, Electron, Transmission
  • Mitochondria / enzymology
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Mutation
  • Osteochondrodysplasias / genetics*
  • Phenotype
  • Protein Structure, Tertiary
  • Proteolysis
  • Serine Proteases / genetics*
  • Serine Proteases / metabolism
  • Tooth Abnormalities / genetics*


  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Serine Proteases
  • ATP-Dependent Proteases
  • LONP1 protein, human

Supplementary concepts

  • CODAS syndrome