title: [Spinocerebellar ataxia type 31].
abstract: Spinocerebellar ataxia type 31 (SCA31) is a relatively common degenerative ataxia in Japan. We recently discovered SCA31 mutation as a complex pentanucleotide repeat containing (TAAAA)(n), (TAGAA)(n), and (TGGAA)(n). The size of this repeat ranged from 2.8 to 3.5 kilo-base pairs (kb). Among these repeats, (TGGAA)(n) repeat appears crucial for SCA31 pathogenesis. The length of this complex repeat inversely correlated with ages of onset in patients. The mutation lies in an intron shared by two different genes, BEAN (brain expressed, associated with NEDD4) and TK2 (thymidine kinase 2), which are transcribed in opposite directions. Thus, the complex pentanucleotide sequence is predicted to be transcribed in both directions, but not necessarily translated into proteins. In situ hybridization analysis in patients' Purkinje cells demonstrated that pentanucleotide repeats transcribed in BEAN direction form RNA aggregates ("RNA foci"). We further found that splicing factors, SFRS1 and SFRS9, binds to (UGGAA)(n), the transcript of (TGGAA)(n) in vitro. These findings may imply that SCA31 conforms to pathogenic mechanisms underlying non-coding repeat disorders, such as myotonic dystrophies (DM1 & DM2), and that SFRS1 and SFRS9 are involved in SCA31 pathogenesis.
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Nozomu
authors.initials: N
authors.lastname: Sato
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Niimi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Amino
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
mesh_terms: D017668:Age of Onset; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics*; D016254:Mutagenesis, Insertional; D000075702:Nedd4 Ubiquitin Protein Ligases; D009419:Nerve Tissue Proteins / Q000235:genetics; D011689:Purkinje Cells / Q000473:pathology; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D013049:Spectrin / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000145:classification / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D013937:Thymidine Kinase / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C503982:PLEKHG4 protein, human; D013049:Spectrin; D012313:RNA; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; C105339:thymidine kinase 2; D013937:Thymidine Kinase