title: Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.
abstract: We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Beryl
authors.initials: B
authors.lastname: Royer-Bertrand
authors.affiliation: Sección Genética, Hospital Clínico Universidad de Chile, and Sección Citogenética, Laboratorio, Clínica Alemana de Santiago, Santiago, Chile.
authors.forename: Silvia
authors.initials: S
authors.lastname: Castillo-Taucher
authors.affiliation: Unidad de Genética, Hospital Regional Rancagua, Rancagua, Chile; and ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Moreno-Salinas
authors.affiliation: Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
authors.affiliation: Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Chae
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Radiology, Woorisoa Children's Hospital, Saemalro, Guro-gu, Seoul 08291, Republic of Korea.
authors.forename: Ok-Hwa
authors.initials: OH
authors.lastname: Kim
authors.affiliation: Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Esra
authors.initials: E
authors.lastname: Dikoglu
authors.affiliation: Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Belinda
authors.initials: B
authors.lastname: Campos-Xavier
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Enrico
authors.initials: E
authors.lastname: Girardi
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.affiliation: Medical Genetics Service, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.affiliation: Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.|Department of Pediatrics and Pediatric Surgery, University of Lausanne and Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics*; D001848:Bone Diseases, Developmental / Q000000981:diagnostic imaging / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*; D009139:Musculoskeletal Abnormalities / Q000000981:diagnostic imaging / Q000235:genetics*; D020125:Mutation, Missense; D011859:Radiography; D013577:Syndrome
chemical_list: D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D024101:Mitochondrial Proteins