Kevin A Strauss,* Robert N Jinks, 3, 14 Erik G Puffenberger, Sundararajan Venkatesh, 4 Kamalendra Singh, 4, 6 Iteen Cheng, 5 Natalie Mikita, 5 Jayapalraja

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 fourLONP1mutations inherited as homozygous or compound-heterozygouscombinations among ten individuals with CODAS syndrome. The individuals come from three different ancestral backgrounds (Amish-Swiss from United States, n¼8; Mennonite-German from Canada, n¼1; mixed European from Canada, n¼1).LONP1encodes Lonprotease, a homohexameric enzyme that mediates protein quality control, respiratory-complex assembly, gene expression, and stressresponses in mitochondria. All four pathogenic amino acid substitutions cluster within the AAAþdomain at residues near the ATP-bind-ing pocket. In biochemical assays, pathogenic Lon proteins show substrate-specific defects in ATP-dependent proteolysis. When ex-pressed recombinantly in cells, all altered Lon proteins localize to mitochondria. The Old Order Amish Lon variant (LONP1c.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, themtDNA-encoded subunit II of cytochrome c oxidase; and (3) reduced spare respiratory capacity, leading to impaired mitochondrial pro-teostasis and function. CODAS syndrome is a distinct, autosomal-recessive, developmental disorder associated with dysfunction of themitochondrial Lon protease.