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.
- 1. Clinic for Special Children, Strasburg, PA 17579, USA; Lancaster General Hospital, Lancaster, PA 17602, USA; Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA. Electronic address: [email protected].
- 2. Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA.
- 3. Clinic for Special Children, Strasburg, PA 17579, USA; Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA.
- 4. Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
- 5. Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Molecular Microbiology and Immunology, Christopher Bond Life Sciences Center, University of Missouri, Columbia, Columbia, MO 65201, USA.
- 6. Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
- 7. Department of Molecular Microbiology and Immunology, Christopher Bond Life Sciences Center, University of Missouri, Columbia, Columbia, MO 65201, USA.
- 8. Auditory Physiology and Psychoacoustics Research Laboratory, duPont Hospital for Children, Wilmington, DE 19803, USA.
- 9. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- 10. Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
- 11. Medical Genetics Program, Department of Pediatrics, Children's Health Research Institute and Western University, London, ON N6C 2V5, Canada.
- 12. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
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.