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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Strauss, KA; Jinks, RN; Puffenberger, EG; Venkatesh, S; Singh, K; Cheng, I; Mikita, N; Thilagavathi, J; Lee, J; Sarafianos, S; Benkert, A; Koehler, A; Zhu, A; Trovillion, V; McGlincy, M; Morlet, T; Deardorff, M; Innes, AM; Prasad, C; Chudley, AE; Lee, INW; Suzuki, CK

Published Date

  • January 2015

Published In

Volume / Issue

  • 96 / 1

Start / End Page

  • 121 - 135

PubMed ID

  • 25574826

Pubmed Central ID

  • PMC4289676

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

International Standard Serial Number (ISSN)

  • 0002-9297

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2014.12.003


  • eng