title: Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome.
abstract: Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored.
authors: Centre des Maladies Moléculaires CHUV, University of Lausanne, Switzerland.
authors: Esra
authors: E
authors: Dikoglu
authors: Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Ali
authors: A
authors: Alfaiz
authors: Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Maria
authors: M
authors: Gorna
authors: Genetics Unit, Instituto da Criança, HC/FMUSP, Sao Paulo, Brazil.
authors: Deborah
authors: D
authors: Bertola
authors: Department of Orthopaedic Surgery, Seoul National Univ Children's Hospital, Seoul, South Korea.
authors: Jong Hee
authors: JH
authors: Chae
authors: Department of Orthopaedic Surgery, Seoul National Univ Children's Hospital, Seoul, South Korea.
authors: Tae-Joon
authors: TJ
authors: Cho
authors: Pediatric Genetics Unit, Department of Pediatrics, Başkent University Faculty of Medicine, Ankara, Turkey.
authors: Murat
authors: M
authors: Derbent
authors: Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey.
authors: Yasemin
authors: Y
authors: Alanay
authors: Division of Pediatric Endocrinology, Department of Pediatrics, Marmara University Hospital, Istanbul, Turkey.
authors: Tulay
authors: T
authors: Guran
authors: Radiology, Woorisoa Children's Hospital, Seoul, Korea.
authors: Ok-Hwa
authors: OH
authors: Kim
authors: Centro de Genética Médica, Instituto Fernandes Fugueira/Fiocruz, Rio de Janeiro, Brazil.
authors: Juan C
authors: JC
authors: Llerenar
authors: Genetics Unit, Instituto da Criança, HC/FMUSP, Sao Paulo, Brazil.
authors: Guillerme
authors: G
authors: Yamamoto
authors: Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Giulio
authors: G
authors: Superti-Furga
authors: Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland.
authors: Alexandre
authors: A
authors: Reymond
authors: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Ioannis
authors: I
authors: Xenarios
authors: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Brian
authors: B
authors: Stevenson
authors: Centre des Maladies Moléculaires CHUV, University of Lausanne, Switzerland.
authors: Belinda
authors: B
authors: Campos-Xavier
authors: Centre des Maladies Moléculaires CHUV, University of Lausanne, Switzerland.
authors: Luisa
authors: L
authors: Bonafé
authors: Department of Pediatrics, CHUV, University of Lausanne, Switzerland.
authors: Andrea
authors: A
authors: Superti-Furga
authors: Medical Genetics Service, CHUV, University of Lausanne, Switzerland.
authors: Sheila
authors: S
authors: Unger
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics*; D001483:Base Sequence; D019465:Craniofacial Abnormalities / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D006618:Hip Dislocation, Congenital / Q000235:genetics*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013557:Switzerland; D014071:Tooth Abnormalities / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; D049069:ATP-Dependent Proteases; C000595973:LONP1 protein, human
keywords: CODAS; LONP1; cataract; mitochondrial protease; skeletal dysplasia