title: A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.
abstract: BACKGROUND
  Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume.
  
  
  RESULTS
  Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis.
  
  
  CONCLUSIONS
  This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy.
authors: Faculty of Science, Laboratory of Drosophila Research, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Ho
authors: H
authors: Tsoi
authors: Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Allen C S
authors: AC
authors: Yu
authors: Faculty of Science, Laboratory of Drosophila Research, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Zhefan S
authors: ZS
authors: Chen
authors: Faculty of Science, Laboratory of Drosophila Research, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Nelson K N
authors: NK
authors: Ng
authors: Faculty of Medicine, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Anne Y Y
authors: AY
authors: Chan
authors: Faculty of Medicine, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Liz Y P
authors: LY
authors: Yuen
authors: Faculty of Medicine, Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Jill M
authors: JM
authors: Abrigo
authors: Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong.
authors: Suk Ying
authors: SY
authors: Tsang
authors: Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Stephen K W
authors: SK
authors: Tsui
authors: Clinical Genetic Service, Department of Health, The Government of Hong Kong, Hong Kong, Hong Kong.
authors: Tony M F
authors: TM
authors: Tong
authors: Clinical Genetic Service, Department of Health, The Government of Hong Kong, Hong Kong, Hong Kong.
authors: Ivan F M
authors: IF
authors: Lo
authors: Clinical Genetic Service, Department of Health, The Government of Hong Kong, Hong Kong, Hong Kong.
authors: Stephen T S
authors: ST
authors: Lam
authors: Faculty of Medicine, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Vincent C T
authors: VC
authors: Mok
authors: Faculty of Medicine, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Lawrence K S
authors: LK
authors: Wong
authors: Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Jacky C K
authors: JC
authors: Ngo
authors: Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Kwok-Fai
authors: KF
authors: Lau
authors: Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong.
authors: Ting-Fung
authors: TF
authors: Chan
authors: Faculty of Science, Laboratory of Drosophila Research, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: H Y Edwin
authors: HY
authors: Chan
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000000981:diagnostic imaging; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D006723:Hong Kong; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011859:Radiography; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology
chemical_list: C580811:CCDC88C protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins
keywords: Clinical Genetics; Neurology