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Huntington Disease-Like 2: the First Patient with Apparent European Ancestry

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Huntington Disease-Like 2: the First Patient with Apparent European Ancestry Clin Genet 2008: 73: 480–485 # 2008 The Authors Printed in Singapore. All rights reserved Journal compilation # 2008 Blackwell Munksgaard CLINICAL GENETICS doi: 10.1111/j.1399-0004.2008.00981.x Original Article Huntington disease-like 2: the first patient with apparent European ancestry Santos C, Wanderley H, Vedolin L, Pena SDJ, Jardim L, Sequeiros J. C Santosa, H Wanderleyb, Huntington disease-like 2: the first patient with apparent European L Vedolinb, SDJ Penac, ancestry. L Jardimb,d and J Sequeirosa,e Clin Genet 2008: 73: 480–485. # Blackwell Munksgaard, 2008 aInstituto de Biologia Molecular e Celular, b Huntington disease-like 2 (HDL2) is a rare autosomal dominant disorder Porto, Portugal, Servicxo de Gene´tica Me´dica do Hospital de Clı´nicas de Porto of the nervous system, apparently indistinguishable from Huntington Alegre, Porto Alegre, Brazil, disease (HD). HDL2 is caused by the expansion above 40 CTG/CAG cDepartamento de Bioquı´mica e repeats, in a variably spliced exon of the junctophilin-3 gene, on Imunologia, Universidade Federal de chromosome 16q24.3. All patients described so far have been of African Minas Gerais, Belo Horizonte, Brazil, ancestry. A clinical evaluation, including the Unified Huntington’s dDepartamento de Medicina Interna, Disease Rating Scale, and brain Magnetic resonance imaging were Universidade Federal do Rio Grande achieved in a 48-year-old Brazilian man of apparent European do Sul, Porto Alegre, Brazil, and eInstituto extraction, and presenting a picture very suggestive of HD. Gene de Cieˆncias Biome´dicas de Abel Salazar, mutation analysis (HD, HDL1, HDL2, dentatorubralpallidoluysian Universidade do Porto, Portugal atrophy and spinocerebellar ataxia 17) was performed. After exclusion of the HD mutation and other HDL disorders, we identified an expansion Key words: ancestry – chorea – of 47 CTG/CAG at the HDL2 locus. To clarify the origin of the DRPLA – haplotype – HDL1 – mutation and estimate the patient’s ancestry, we performed haplotype Huntington disease – SCA17 studies and used the insertion/deletion polymorphisms method. Despite the fact that this patient had an estimated likelihood of 97.4% of being of Corresponding author: Cla´udia Santos, European ancestry, the haplotype containing the expanded allele has PhD, Instituto de Biologia Molecular e Celular, R. Campo Alegre, 823, been found only in Africans. Thus, this is the first HDL2 case reported in 4150-180 Porto, Portugal. a patient with an apparent European ancestry, although bearing an Tel.: 1351 22 607 49 40; African HDL2 haplotype. This work stresses the importance of fax: 1351 22 609 91 57; performing the diagnosis of HDL2 in HD-like patients of various e-mail: [email protected] ethnicities, and particularly in highly mixed populations. Received 27 December 2007, revised and accepted for publication 28 January 2008 Huntington disease-like 2 (HDL2) (OMIM 606438) (DRPLA) and SCA17, may also have overlap- is a newly described disorder of autosomal domi- ping symptoms with HD, namely Parkinsonism, nant inheritance, the symptoms of which may dementia, chorea and dystonia (3). be undistinguishable from Huntington disease HDL2 has not yet been found among Europeans (HD) (OMIM 143100). HD is a disorder of the (4–7) or Asians (8). HDL2 is the result of an central nervous system, characterized by invol- expanded CTG/CAG repeat, in the junctophilin-3 untary choreic movements, progressive motor gene (JPH3), on chromosome 16q24.3 (6). Normal impairment, behavioural anomalies and cognitive individuals have 6–28 repeats, whereas the mu- decline. tated gene in patients contains 40–59 repeats (8). HDL2 belongs to a group of HDL disorders, The pathogenic mechanism underlying HDL2 also including HDL1 (OMIM 603218), an auto- remains elusive. Different JPH3 transcripts be- somal dominant disease caused by an extra octa- cause of alternative splicing and different polya- peptide repeat in the prion protein gene (PRNP), denylation sites have been described (6). The on chromosome 20p12 (1); and HDL3 (OMIM CTG/CAG tract may be located in intron 1 of 604802), an autosomal recessive, mapped to 4p15.3 the first isoform described (9) or within an alter- (2). Furthermore, two dominant spinocerebellar natively spliced exon (exon 2A), either untrans- ataxias (SCAs), dentatorubralpallidoluysian atrophy lated or translated to a polyleucine or to a 480 HDL2 in a patient of apparent European ancestry polyalanine stretch (6). The JPH3 gene encodes ously published (6, 13–15), with modifications to for junctophilin-3, a protein predominantly ex- permit automated fluorescent genotyping. For- pressed in the brain (9, 10). The function of ward primers were labelled at its 5# end, with the JPH3 is related to the formation of the junc- fluorochromes 6-FAM or HEX. Polymerase chain tional membrane structure in excitable cells, by reaction (PCR) was performed in a final volume interacting with the plasma membrane, through of 25 ml, containing Taq buffer 13 (Applied its cytoplasmic region and spanning the endo- Biosystems, Foster City, CA), 200 mM deoxyri- plasmic/sarcoplasmic reticulum membrane bonucleotide triphosphate (dNTPs), 1 mM through its C-terminal hydrophobic region (10). MgCl2, 400 nM each primer, 1.5 U Taq Gold The JPH3 knockout mouse shows impaired (Applied Biosystems) and 10% dimethyl sulfo- performance of motor-coordination tasks, likely xide (DMSO). Fragment separation was made because of abnormal neuronal signalling (11). using capillary electrophoresis in an ABI Despite the above evidence, the involvement of PRISM 310 Genetic Analyser; 1 ml of each the mutant JPH3 in HDL2 pathogenesis has PCR was mixed with 12 ml of deionized form- not yet been fully clarified. By contrast, a recent amide and 0.5 ml GeneScan Rox 500 labelled study showed that the CUG repeat-containing marker (Applied Biosystems). PCR products RNA foci are sufficient to cause cell toxicity in were denatured at 95°C for 2 min, prior to the HDL2 (12). run. The presence of the eight extra octapeptide In this work, we describe the first Brazilian repeats on PRNP gene was analysed by PCR, HDL2 family. Given that the Brazilian popula- followed by an agarose gel (16). tion was originally formed from three ancestral roots (Amerindians, Europeans and Africans), we decided to study the patient’s ancestry. We Haplotype study: DNA cloning and sequencing have also performed a haplotype analysis to try to determine the origin of the mutated allele. We analysed the HDL2 repetitive tract and a downstream region of 6.2 kb, using primers L237-2 5#-agatgccaccgcattcgg-3# and JPH3R 5#- # Subjects and methods gcacatggcagtgaccagcatgg-3 . From the HapMap database (www.hapmap.org), we selected four Subject single nucleotide polymorphisms (SNPs) encom- A 48-year-old male was the fourth child of non- passed within the analysed region: rs2562059, consanguineous parents. The family, which was rs1864151, rs1864152 and rs2573124 (chromo- of Brazilian origin, stated that they were not some positions 86196356, 86199494, 86199574 aware of any African ancestry, even many gener- and 86201418). These SNPs are located 920, ations before. 4059, 4140 and 5985 bp away from the end of His father, already deceased, had a similar clini- the CTG segment. In accordance to the HapMap cal picture since age 50 years, suggesting an database, these are the best SNPs in the region autosomal dominant transmission in this family. taking into account their power of discrimination All his five sibs were asymptomatic; he had three between European and African populations. The asymptomatic offspring (aged 26, 24 and rs2562059 alleles C/G have a relative frequency 22 years). The patient was neurologically exam- of 0.6/0.4 in Europeans and 0.267/0.733 in Afri- ined, and a blood sample was obtained after cans; the rs1864151 alleles A/C have frequencies informed consent. After the initial evaluation, he of 0.617/0.383 in Europeans and 0.525/0.475 in suffered a cerebral vascular accident, with sec- Africans; the rs1864152 alleles A/C have frequen- ondary infections, and died in a septic state, cies of 0.158/0.842 in Europeans and 0.208/0.792 without further neurological evaluation. in Africans; and the rs2573124 alleles C/A have frequencies of 0.602/0.398 in Europeans and 0.271/0.729 in Africans. The PCR assay was performed in a 50 mlfinal Mutation analysis volume of 13 Expand High Fidelity Buffer Genomic DNA was extracted from blood lym- (Roche Applied Science, Mannheim, Germany), phocytes by standard methods. Repeat expan- 200 mM dNTPs, 300 nM of each primer, 10% sions causing HD, as well as other related DMSO, 125 ng of genomic DNA and 2.6 U of disorders (HDL2, DRPLA and SCA17), were Expand High Fidelity enzyme mix (Roche). screened in the proband. Trinucleotide repeats in Cycling conditions were performed according the HD, JPH3, ATN1,andTBP genes were ampli- to the manufacturer’s instructions (Expand High fied using primers and cycling conditions previ- Fidelity PCR System). DNA fragments were 481 Santos et al. purified using a kit (Amersham Biosciences, a widebased, slow and interrupted by choreic Buckinghamshire, UK) after excision of DNA movements of his legs and trunk. There was agarose bands. dysarthria, motor impersistence, dysmetria, and By cloning the purified DNA fragments (6.2 dysdiadocokinesia; his ocular pursuit was inter- kb) into the pCR4-TOPO vector (Invitrogen, rupted. Deep tendon reflexes were normal. Cho- Carlsbad, CA), under the manufacturer’s instruc- rea was important in the tongue, trunk, upper tions, we obtained isolated
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