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Identification of the Gene Responsible for a Novel Form of Congenital Cerebellar Ataxia

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Identification of the Gene Responsible for a Novel Form of Congenital Cerebellar Ataxia Ge neratio ns The Official Publication of the National Ataxia Foundation Volume 36, Number 3 Fall 2008 Iden tification of the Gene Respon sible for a Novel Form of Congenital Cerebellar Atax ia By Alfredo Brusco, PhD University of Torino, Torino, Italy The following is a research summary of a grant funded by NAF for fiscal year 2007. Congenital forms of ataxia are predominantly walking (15 months) with motor incoordination, non-progressive syndromes characterized by and unsteady gait. Brain MRI at two years hypotonia, developmental delay, and delayed revealed hypoplasia of the posterior fossa, and motor milestones that precede the typical hypotrophy of the cerebellar hemispheres and cerebellar symptoms. The role of the cerebellum the cerebellar vermis. The MRI was repeated at in certain cognitive functions and in particular six years and 10 years and did not show peculiar its connection to the frontal lobe are very changes. Mild dysmorphic features were anno - important for development of language and tated at six years; at eight years she showed a gait some cognitive tasks (Leiner et al. 1993). There - and limb ataxia, dysmetria and adiadochokinesia fore it is not surprising that children with with moderate mental retardation and visual cerebellar dysfunction typically show marked and spatial orientation disorders. Blood samples delay in language acquisition and other param- were obtained from the girl and her parents; eters of cognition such as planning strategies and a lymphoblastoid cell line (LCL) and a fibroblast attention. culture were established for the proband. Classification of congenital forms is still Written informed consent was obtained from un certain and difficult. Most patients with the parents for diagnostic and research purposes. pure non-progressive congenital cerebellar ataxia The patient come to our attention because have a sporadic form of unknown heredity and of an abnormal karyotype, with a de-novo, aetiology. apparently balanced, translocation involving In the present project we studied a 10-year- chromosomes X and 8: 46,X, t(X;8)(q24;q24.3). old girl affected by cerebellar ataxia, mild Using genomic DNA extracted from lympho - mental retardation, and facial dysmorphism. The symptoms appeared when the proband started Continued on page 3 Page 2 Generations Fa ll 2008 Please direct correspondence to: Gen erations Staf f: National Ataxia Foundation Julie Braun ..................................... Financial Director 2600 Fernbrook Lane, Suite 119 Sue Hagen ........................... Patient Services Director Minneapolis, MN 55447-4752 Mike Parent ................................... Executive Director Phone: (763) 55 3- 0020 Lori Shogren ................... Special Projects Coordinator FAX: (763) 55 3- 0167 Liz Werner ................................ Outreach Coordinator Internet: www.ataxia.org Design, Production and Printing .............. Leader Printing E-mail: [email protected] Generations is published by the National Ataxia Foundation, Inc., Minneapolis, MN. Copyright 2008 by the National Ataxia Foundation, Inc. All rights reserved. We ask that other publications contact us for permission to reprint any article from Generations . Disclaimer The National Ataxia Foundation does not endorse products, services, or manufacturers. Those that are mentioned in Generations are included only for your information. The NAF assumes no liability whatsoever for the use or contents of any product or service mentioned in the newsletter. Table of Conten ts Annual Membership Meeting Research & Education (cont.) 2009 Annual Membership Meeting ... 16, 2 4- 29 The Role of P/Q Calcium Channel Fragments in SCA6 Pathogenesis ................. 18 Research & Education Generation of Improved Mouse Models Regulatory Analysis of Friedreich Ataxia of FRDA for Pharmacological Testin g ............ 19 Locus Using BAC Genomic Reporters .............. 5 Articles Phosphorylation of Ataxin-3 Implication for Cellular Localization and Viability ............... 5 Meet the New Staff Members at NAF .............. 4 The Role of the Human P/Q Type Calcium From the Desk of the Executive Director .......... 8 Channel in the Pathogenesis of Ataxia ............ 6 Life Planning – The Financial Piec e ............... 13 A Multicenter Pilot Study of the The Immune Response in the Ataxia Web-Based National Ataxia Database ............. 6 Associated with Gluten Sensitivity ................. 20 Effects of Polyglutamine Expansion Dr. Bronya Keats Retires on Activity of Ataxin-3, the from Position at LSUHSC ............................. 30 Spinocerebellar Ataxia 3 Disease Protein ........ 7 Frequently Asked Questions Examination of the Underlying About Tissue Donation ................................. 31 Mechanism of p53 Mediation of the Interview: Rebecca Cummings Baldwin, Ataxia-Telangiectasia Mutant (ATM) Author of “Three Wheels” ............................. 32 Signaling Pathway .......................................... 9 Two Kyle Bryant Translational Development of Histone Deacetylase Research Grants Awarded ............................ 47 Inhibitors as Therapeutics for FRDA ............... 11 Membership Topics Deranged Calcium Signaling in SCA3 Neurons ........................................ 12 Chapter and Support Group News ................ 33 Molecular Mechanism of NAF Merchandise ........................................ 37 Transcription Alterations in SCA1 .................. 14 NAF Chapters, Support Groups Molecular Characterization of Purkinje and Ambassadors Listings ........................... 38 Cell Function in Mice Carrying Deletions Calendar of Events ...................................... 44 of the SCA8 Ataxia Locus ............................ 17 Memorials and In Your Honor ....................... 46 Fa ll 2008 Generations Page 3 Identification of the Gene .. lymphoblast from the patient by RT-PCR. We Continued from page 1 also tested the expression of CUL4B and GRIA3, which were shown to be mutated in pa - cytes, we showed that X-inactivation was tients with mental retardation, although they are skewed. The proband’s inactive X-allele was at more than 200 Kb away from the breakpoint. inherited from the mother. This means, firstly, Both genes showed a normal expression in the that the active chromosome X underwent a patient’s LCL. 2) the breakpoint on 8q24.3 maps translocation in the paternal germline and sec - between exons 2 and 3 of a known gene, whose ondly, that a mutation in an X-linked recessive name is reserved. The breakpoint inactivates one gene can be excluded because in this case the of the two alleles, as shown by RT-PCR analy - father would have manifested the phenotype. sis: sequencing of the complete cDNA in the pa - Segregation analysis using the “Profiler tient’s LCL demonstrates the presence of a single Plus kit” (Applied Biosystems, 9 polymorphic transcript because a heterozygous polymorphism markers in the genome) confirmed paternity/ in the 3’-UTR of the gene was expressed from a maternity. single allele. Furthermore, no other nucleotide We performed FISH analysis on the patient’s substitution was present in the expressed allele, metaphase spreads with BAC/PAC clones ruling out the possibility of an autosomal reces - covering 8q24.3 (16 clones) and Xq24-25 (18 sive disease due to the translocation combined clones). The breakpoint was located in a region with a point mutation. of ~33 Kb on chromosome 8 and ~37 Kb on To verify if the translocation was associated chromosome X. with other cytogenetic abnormalities, we used We used a set of equally spaced forward and re - CGH analysis using a 244K chip (Agilent Tech - verse primers to amplify the breakpoint junctions nologies). No further genomic deletion/duplica - on the two derivatives. One couple of primers tion was revealed, proving that the translocation for each derivative allowed us to amplify the occurred without gross genomic losses. Overall junction fragments. Sequencing showed that the these data were necessary to exclude other breakpoint is located within two repetitive possible genetic causes of the disease, besides the elements both on chromosome 8 (MER4/AluJ) translocation. Finally, using Taqman Real-Time and X (SVA element); no homology is present at PCR we proved that in LCLs the mRNA levels the junction; a intergenic region of 500bp was of the gene are approximately one half of normal lost in the translocation on the X chromosome. controls. The identification of the precise breakpoint on In summary our work identified the break - both the chromosomes 8 and X showed that: 1) points of an X;8 translocation in a girl with no known gene is interrupted by the transloca - ataxia, cerebellar hypoplasia and mental retarda - tion on the X chromosome. The closest genes tion, and showed that the disease may be due are located approximately 110 Kb both upstream to a haploinsufficiency of one gene located on (THOC2 ) and downstream of the breakpoint chromosome 8. A mouse model for this gene is (BIRC4 ). Functional studies in yeast suggests available. The homozygous knock-out animals that THOC2 physically links proteins that func - are non-viable, but no phenotype or cerebellar tion in mRNA export or transcription, whereas anomalies were noted in heterozygotes. BIRC4 is a member of a family of proteins which However, the interrupted gene is important in inhibits apoptosis through binding to TRAF1 cellular adhesion, migration, and it was found to and TRAF2 proteins. We showed that the ex - pression of these genes is maintained in cultured Continued on page
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