title: Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.
abstract: The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.
authors: Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors: Monika B
authors: MB
authors: Hartig
authors: Arcangela
authors: A
authors: Iuso
authors: Tobias
authors: T
authors: Haack
authors: Tomasz
authors: T
authors: Kmiec
authors: Elzbieta
authors: E
authors: Jurkiewicz
authors: Katharina
authors: K
authors: Heim
authors: Sigrun
authors: S
authors: Roeber
authors: Victoria
authors: V
authors: Tarabin
authors: Sabrina
authors: S
authors: Dusi
authors: Malgorzata
authors: M
authors: Krajewska-Walasek
authors: Sergiusz
authors: S
authors: Jozwiak
authors: Maja
authors: M
authors: Hempel
authors: Juliane
authors: J
authors: Winkelmann
authors: Matthias
authors: M
authors: Elstner
authors: Konrad
authors: K
authors: Oexle
authors: Thomas
authors: T
authors: Klopstock
authors: Wolfgang
authors: W
authors: Mueller-Felber
authors: Thomas
authors: T
authors: Gasser
authors: Claudia
authors: C
authors: Trenkwalder
authors: Valeria
authors: V
authors: Tiranti
authors: Hans
authors: H
authors: Kretzschmar
authors: Gerd
authors: G
authors: Schmitz
authors: Tim M
authors: TM
authors: Strom
authors: Thomas
authors: T
authors: Meitinger
authors: Holger
authors: H
authors: Prokisch
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D015331:Cohort Studies; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: C568481:C19orf12 protein, human; D024101:Mitochondrial Proteins; D007501:Iron