title: CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease.
abstract: 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.
authors.affiliation: 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: kstrauss@clinicforspecialchildren.org.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.affiliation: Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jinks
authors.affiliation: 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.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Sundararajan
authors.initials: S
authors.lastname: Venkatesh
authors.affiliation: 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.
authors.forename: Kamalendra
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Iteen
authors.initials: I
authors.lastname: Cheng
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Mikita
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Jayapalraja
authors.initials: J
authors.lastname: Thilagavathi
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Molecular Microbiology and Immunology, Christopher Bond Life Sciences Center, University of Missouri, Columbia, Columbia, MO 65201, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sarafianos
authors.affiliation: 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.
authors.forename: Abigail
authors.initials: A
authors.lastname: Benkert
authors.affiliation: Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA.
authors.forename: Alanna
authors.initials: A
authors.lastname: Koehler
authors.affiliation: Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA.
authors.forename: Anni
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Trovillion
authors.affiliation: Department of Biology and Biological Foundations of Behavior Program, Franklin and Marshall College, Lancaster, PA 17603, USA.
authors.forename: Madeleine
authors.initials: M
authors.lastname: McGlincy
authors.affiliation: Auditory Physiology and Psychoacoustics Research Laboratory, duPont Hospital for Children, Wilmington, DE 19803, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Morlet
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Deardorff
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Medical Genetics Program, Department of Pediatrics, Children's Health Research Institute and Western University, London, ON N6C 2V5, Canada.
authors.forename: Chitra
authors.initials: C
authors.lastname: Prasad
authors.affiliation: 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.
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Irene Nga Wing
authors.initials: IN
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Suzuki
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics*; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006130:Growth Disorders / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006618:Hip Dislocation, Congenital / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D057057:Serine Proteases / Q000235:genetics* / Q000378:metabolism; D014071:Tooth Abnormalities / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D057057:Serine Proteases; D049069:ATP-Dependent Proteases; C000595973:LONP1 protein, human