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.

Kevin A Strauss ¹, Robert N Jinks ², Erik G Puffenberger ³, Sundararajan Venkatesh ⁴, Kamalendra Singh ⁵, Iteen Cheng ⁶, Natalie Mikita ⁶, Jayapalraja Thilagavathi ⁴, Jae Lee ⁴, Stefan Sarafianos ⁷, Abigail Benkert ³, Alanna Koehler ², Anni Zhu ², Victoria Trovillion ², Madeleine McGlincy ², Thierry Morlet ⁸, Matthew Deardorff ⁹, A Micheil Innes ¹⁰, Chitra Prasad ¹¹, Albert E Chudley ¹², Irene Nga Wing Lee ⁶, Carolyn K Suzuki ⁴

Affiliations

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.

PMID: 25574826 DOI: 10.1016/j.ajhg.2014.12.003

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.

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