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Genetic Localisation and Molecular Characterisation of Genes for Inherited Ataxias

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Genetic Localisation and Molecular Characterisation of Genes for Inherited Ataxias €)-t- o\ Genetic localisation and molecular characterisation of genes for inherited ataxias A thesis submitted for the degree of Doctor of Philosophy to the Uníversity of Adelaide by Kathryn Louise Friend (BSc) School of Medicine Department of Paediatrics, Womerls and Children s Hospital Adelaide July 2000 i Addendum Page iv; line 5: ARGF should read AGRF Page 21-; Change 4Í a" last patagraph to read: The identification of a disease causing mutation Tttiulty allows the assessment of mutations in this gene in other families with identical clinical symptoms. Identification of additional mutations will indicate genetic heterogeneity / homogenerty and further, provides appropriate confirmation of carier s tatus, presymptomatic and prenatal diagnosis Page 30; lines 9,L0,1L: Replace (AGC)" with (CAG)" Page 32; line L1: Replace Becher er al. 1997 with Irkeuchi et al. j.995 Page 35; end of line 25: Add - Anticipation was originally thought to be an artefact of Sgcertfn_ment (Peruose 1'945) and although the identification of triplet repeats identified a biological explanation it is possible that the apparent anticipÃtion seen in some families may still be due to ascertainment bias. Page 39; line 25: Replace inheritance with phenotype Page 40; end of last line: Add - (reviews; Hackam et aI. 1998; Paulson 1999; see Table ü-s) Page 54; line 3: Replace an with and Page 61; line 91: Replace are with of Page 79;line 1: Table 3-2 should read Table 3-6 Page 93; line L: Replace exclude with EXCLUDE Page 95; lines 28 and 29; Replace a strong hint of linkage with linkage Page'l'1'4; line 5: After undeterrrined., add - Sporadic cases of FHM may not be due to genetic defect. Page1,27; line 16: Replace (Table 5-1a) with (Table S-3) Page 1,31,; line 24: Replace (Table S-9) with (Table S-Z) last paragraph with - In summary, the xperiments and RED assay failed to give be responsible for the symptoms in S-CA Page1,68;1ine 12: Replace is with are Page 181; line 25: Add The individual in which the homozygous expansion at the FRDA locus was detected was subsequently deemed to have typical FRDA with later onset. Page 201.; ltne7 Add - Ikeuchi T, Koide R, Onodera O, Tanaka H, Oyake M, Takano FI, Tsuji S Dentatorubral-pallidoluysian atrophy (DRPLA). Molecular basis for wide clinical features of DRPLA. Clin Neurosci \995;3(1):23-7 Page 209; line 4 Add - Penrose LS The problem of anticipation in pedigrees of dystrophia myotoníca. Arìn Eugenics1'4:\25 -132. Response to reviewers comments Page 71,; Response to reviewer - Assumption of equal allele frequencies does not significantþ change lod scores attained thus it is valid to use equal allele frequencies. Page 92; Response to reviewer - The individual in question is coded as unlcrown for linkage analysis has phenotype which can be attríbuted to a car accident thus it is more valid to assign an urilmowïr phenotype rather than to assume this person to be a phenocopy. Pages 1.05,1.07; Response to reviewer - It is acknowledged that there are at least three loci for FHM. The intention of the candidate is to highlight the phenotypic heterogeneity for the CACNALA gene and to question whether other genes will be involved in these disorders with similar phenotypic heterogerreity. Page 109; Response to reviewer - Penetrance refers to expression of symptoms rather than variability of phenotype. Thus, in these pedigrees the penetrance is complete although the phenotype may vary. Page\L2; Response to reviewer - All othet affected individuals in EA-2 family (family 1) have episodic ataxia and no migraine. Individual III.1 has only migraine and thus most likely represents a variant phenotype. Given the early onset of episodic ataxia and the áge of this individual (33 years old) it ís not likely that this individual is presymptomatic, although it is possible that IIL1 may develop episodic ataxia. Acknowledgments I wish to thank all my colleagues in the Depattment of Cytogenetics and Molecular Genetics (WCH) for their ongoing support and friendship during these studies. In particular I thank: Marie Mangelsdorf for friendship, moral support, useful discussions and advice, meals at the pub late in the everring and pouring acrylamide gels at the end of the day; Hilary Phillips, Robyn Wallace and Georgina Hollway for their friendship, useful discussions and organisation of the microsatellite primer dilutions; Jo Crawford" Agi Gedeon, Oliva Handt, Sonia Dayans, Merran Finnis, Llmne Hobson, Scott Whitmore, Elizabeth Baker, Helen Eyre Erica Woollatt and Rosalie Smith for their friendship, words of wisdom and advice and good cheer during these studies - it was always a pleasure to share my working day with these people. I also wish to thank my supervisors Rob Richards and Grant Sutherland for discussions and critical appraisal of this thesis, John Mulley for useful and helpful discussions on linkage analysis and Liz Thompson for advice and proof reading of clinican aspects of this thesis. I thank the various clinicians, particularþ Drs E. Haan, G Suthers and E. Thompson and Ms S. White, for collecting family material and making it available for our use, and to the families themselves for their co-operation. I thank my parents for their encolüagement, support and love during these studies. Most importantly, I wish to sincereþ thank my husband, best friend and colleagae,lozef. Gecz lor his undying patience, love, inspiratiorç words of encouragement and support and always useful and informative discussions. And fi.,ully to our delightful daughter, Ellen, for her 40 minute naps which made finishing off this thesis take longer than I anticipated, and for her wonderful smiles which made me realise that it didn't matter. iii List of abbreviations The following list contains abbreviations used throughout the thesis: A adenosine Ab antibody ADCA autosomal dominant cerebellar ataxia ARGF Australian Genome Researdr Facility BAC bacterial artificial chromosome Blast Basic local align:rrent search tool bp base pair C cytosine cDNA complementary DNA CEPH Centre d'Etude de Polymorphism Humain CHCL Cooperative lfuman Linkage Centre cM centiMorgan dATP deoxy adenosine triphosphate dCTP deoxy cytosine triphosphate dGTP deoxy guanosine triphosphate DIRECT Direct identification of repeat expansions cloning technique DM myotonic dystrophy DNA deoxyribonucleic acid DRPLA Dentatorubral pallidoluysian atrophy dTTP deoxy thymidine triphosphate EA-1 episodic ataxia type 1 EA-2 episodic ataxia type2 EST expressed sequence tags FHM familial hemiplegic migraine FRDA Friedreich ataxia HD Huntington fisease IMVS Institute for Medical and Veterinary Science IOSCA Infantile onset of spinocerebellar ataxia LCL lymphoblast cell line Mb megabase MDE mutation detection enhancement MJD Machado-Joseph disease MRI magnetic reson€rnce i-ug-g NCBI national centre for biotechnology information NPCA non progressive cerebell,ar ataxia PAC PL artificial chromosome PCR polymerase chain reaction PIC polymorphic information content RACE rapid amplification of cDNA ends RED repeat expansion detection RFLP restriction fragment length polymorphism SBMA spinal-bulbar muscular atrophy scA (1-L0) spinocerebellar ataxia (1-10) SNP single nucleotide polymorphism sscA/P single strand conformation analysis / polymorphism URL uniform resource locatíon WB western blot WCH Women's and Childrerfs Hospital YAC yeast artificial chromosome iv SUMMARY: Inherited ataxias are genetically and clinically heterogeneous. They can be divided into several categories based on the following: inherited ataxias resulting from metabolic dysfunctiorç congenital ataxias, early onset ataxias and late onset ataxias. The last three groups, that is, the congenital, early and late onset ataxias are those which were examined in detail in this thesis. The congenital ataxias or non-progressive congenital ataxias (NPCAs) can be divíded into two groups, syndromal and pr;re. Although several gene localisations for the syndromal forms were lcrown when this study commenced no localisations for the pure NPCAs had been identified. DNA from a large family (PKS0248) segregating NPCA was collected and the gene localised by tinkage to the short arm of chromosome 3 (*itt a maximum two point lod score of 4.26 at 0:0 for D3S3630), Recombinant events in the family map the gene to an 18.9cM region distal to D3S1304. This represents the first genetic localisation for an autosomal dominant pure congenital ataxia. The candidate genes within this region are; inositol 1,4,5 -tiphosphate receptor type L (ITPRI), neural cell adhesion molecule (CALL) and plasmacytoma - associated neuronal glycoprotein (PANG), although these ate yet to be screened for mutations. It is anticipated that a mutation will be detected in one of these genes thus enabling molecular diagnosis for NPCA. The early onset ataxias include Friedreich ataxia, episodic ataxias and several cerebellar ataxias with distinct associated syndromal features. Nonsense mutations in CACNALA (a calcium charurel subunit) have been shown to cause episodic ataxia type 2 (EA-2). Interestingly, it has also been found that mutations in the same gene cause a late onset ataxía, SCA6, and familial hemiplegic migraine (FHM). Two mutations were identified in the CACNALA geneduring the course of these studies. The first of these was identified in a family with familial hemiplegic migraine. The mutation characterised in this family had been previously identified and reported in several other families and thus confirmed that this mutation was recurrent. The second mutation, identified in a family segregating Í.or EA-2, was a novel missense mutation in exon 32 of the CACNAI,A gene. This mutation represents the first missense mutation described for EA-2. It is intriguing that one individual in the family inherits the mutation and accompanying 'affected' haplotype but experiences V migraine alone, with no apparent symptoms of EA-2. This finding expands the spectrum of mutations shown to be responsible for EA-2. The final section of the thesis deals with the late onset spinocerebellar ataxias. This group of ataxias is the most genetically heterogeneous with eleven localisations identified by linkage studies.
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