Noc05008 1257 1262.Pdf

ORIGINAL CONTRIBUTION Mapping of Autosomal Dominant Cerebellar Ataxia Without the Pathogenic PPP2R2B Mutation to the Locus for Spinocerebellar Ataxia 12

Kazunori Sato, MD; Ichiro Yabe, MD, PhD; Yoko Fukuda, PhD; Hiroyuki Soma, MD, PhD; Yasuo Nakahara, MD, PhD; Shoji Tsuji, MD, PhD; Hidenao Sasaki, MD, PhD

Objectives: To map the disease locus and to identify a Results: One locus on chromosome 5q had a multipoint gene mutation in a Japanese family with autosomal domi- logarithm of odds score of 2.408, the theoretical maximum. nant cerebellar ataxia. This locus was flanked by markers rs681591 and rs32582 and includes PPP2R2B (protein phosphatase 2, regulatory Design: A genome-wide linkage analysis was per- subunit B, beta isoform), the causative gene of autosomal formed using the Affymetrix genome-wide human dominant spinocerebellar ataxia 12 (SCA12). However, single-nucleotide polymorphism array containing 909 622 unlike SCA12, no CAG repeat expansions in the promoter single-nucleotide polymorphisms. Direct nucleotide region and no nucleotide substitution or insertion-deletion sequencing of a candidate gene was performed. mutations in the exons of the PPP2R2B gene were found.

Setting: Hokkaido University Graduate School of Medi- Conclusion: Autosomal dominant cerebellar ataxia map- cine and Tokyo University Graduate School of Medicine. ping to 5q31-q33.1 has no CAG repeat expansion or other mutations of the PPP2R2B gene. Patients: Four affected and 6 healthy individuals in a family with autosomal dominant cerebellar ataxia. Arch Neurol. 2010;67(10):1257-1262

PINOCEREBELLAR ATAXIAS density throughout the genome and are as- (SCAs) are hereditary neuro- sociated with lower genotyping error than degenerative disorders that microsatellite markers.4 It has been cal- mainly affect the cerebellum culated that a map of 700 to 900 SNPs is and spinal cord. However, they equivalent to the current 300 to 400 mi- are clinically and genetically heteroge- crosatellite marker sets.5 S 1 neous entities. Although almost 30 gene loci Recent technological advances have per- have been described, the causative genes mitted the use of microarray-based, high- have been identified in nearly half.1 Spino- throughput genotyping for genome-wide cerebellar ataxia 29 has been registered with linkageanalysisusingalmost1millionSNPs. the Online Mendelian Inheritance in Man This method not only markedly reduces database; however, the disease locus and genotypingtimeandcost,butitextractscon- causative gene have not been identified in siderablymoreinformationandoffersgreater many autosomal dominant cerebellar ataxias power than sparse maps of conventional mi- (ADCAs). crosatellite markers in linkage analysis and Previously, linkage analysis for the map- is also useful in small families.6 ping of disease loci has been performed Since 1985, we have followed up a small using polymerase chain reaction–based mi- Japanese family with ADCA. For screen- crosatellite markers. This approach has been ing of disease loci in this family, we per- powerful, especially in mapping mende- formed 2-point linkage analysis using maps lian single-gene disorders such as ADCAs. of about 400 microsatellite markers and However, these markers are sparse in ge- obtained a maximum logarithm of odds nomic DNA (approximately10 cM) and (LOD) score of 2.39 between D5S436 and Author Affiliations: therefore have been underpowered in lim- D5S2014 on chromosome 5q using the Departments of Neurology, ited pedigree structure.2 Likelihoods in Pedigrees program (data not Graduate School of Medicine, After the discovery of single-nucleo- shown). However, another lesion could not Hokkaido University, Sapporo (Drs Sato, Yabe, Soma, and tide polymorphisms (SNPs), more than 3.1 be excluded completely because of sparse Sasaki), and Graduate School of million SNPs have been identified in hu- mapping of the microsatellite markers. 3 Medicine, University of Tokyo, mans to date. Although SNPs are bialle- Therefore, to investigate more precisely the Tokyo (Drs Fukuda, Nakahara, lic and have lower heterozygosity than mi- disease loci and causative gene of the and Tsuji), Japan. crosatellite markers, they exist at a greater ADCA in this family, we performed a ge-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 I-1 I-2 rs Code 11745319 12 12 12655088 1111 681591 1122 10477291 11 12 10050400 11 12 Centromeric 6867036 11 22 boundary area 381658 11 12 455117 222 1 10055590 11 12 381084 211 1 7703926 22 22 340055 12 22 13189362 11 11

13167468 22 22 880770 11 22 4705377 22 11 4705380 11 11 1030176 11 22 17653473 12 11 17110447 11 22 Teromeric 17600568 22 22 boundary area 32587 22 11 741580 22 11 32582 21 22 10491361 22 22 32579 21 21

II-1 II-2 II-3 II-4 II-5 II-6 II-7 II-8 II-9 rs Code 11745319 222 2 2211 2 222 11 2 2 11 12655088 111 1 11 11 11 11 11 11 1 1 681591 22 2 2 22 1 2 1 2221 2 1 2 11 10477291 12 1 2 12 1 2 11221 2 1 2 III-1 11 10050400 12 1 2 12 1 2 1 2 1 2 1 2 1 2 1 1 6867036 12 1 2 12 1 2 1 2 1 2 1 2 1 221 381658 12 1 2 1 2 1 2 1 2 1 2 1 2 1 2 11 455117 21 2 1 2 1 2221111122 2 2 10055590 12 1 2 1 2 1 2 1 2 1 2 1 2 1 2 11 381084 11 1 1 1 1 2 1 2 1 11 21 21 1 1 7703926 22 2 2 2 2 22 2 2 22 2 2 2 2 2 2 340055 22 2 2221 2 1 2 22 1 2 1 2 2 2 13189362 11 1 11111 1 1 11 11 11 11

13167468 22 22 22 22 2 2 22 2 2 2 2 2 2 880770 12 1 2 12 1 2 1 2 1 2 1 2 1 2 1 2 4705377 21 21 2 1 2 1 2 1 2 1 21 21 2 1 4705380 11 1 1 11 11 11 11 11 11 11 1030176 12 1 2 12 1 2 1 2 1 2 1 2 1 2 12 17653473 21 21 2 1 11 11 2 1 11 11 2 1 17110447 12 1 2 12 1 2 1 2 1 2 1 2 1 2 12 17600568 22 22 22 22 2 2 22 2 2 2 2 2 2 32587 21 21 2 1 2 1 2 1 2 1 21 21 2 1 741580 21 21 2 1 2 1 2 1 2 1 21 21 2 1 32582 12 1 2 12 1 2 2 2 1 2 2 2 2 2 12 10491361 22 22 22 22 2 2 22 2 2 2 2 2 2 32579 11 1 2 11 11 2 1 11 21 21 12

Figure 1. Modified pedigree, genotypes, and haplotype construction using single-nucleotide polymorphism (SNP) markers on centromeric and teromeric boundary areas. Circle indicates female individuals; square, male; open diamond, unaffected age–at-risk individual; and slash, deceased. Solid symbols show affected individuals. The SNP markers (rs codes) are given in the left column in consecutive order (centromeric q-arm on top). Genotypes are described numerically in the boxes, and the haplotypes are shaded with different colors. The genotypes and haplotypes of individual I-1 are deduced from those of other family members. Based on logarithm of odds (LOD) scores from pairwise parametric analysis, the centromeric and teromeric boundary of the candidate locus defined by the recombination between adjacent SNPs is shown with the rs codes in blue lettering. The haplotype segregating with the disease is shaded in red. Because individual I-1 has homozygotic genotypes in the boundary areas (boxed sections), the recombination site in the same areas in offspring II-4 and II-9 could not be identified. Therefore, the precise boundaries of the candidate locus could not be determined by haplotype analysis.

nome-wide linkage analysis using microarray-based, high- unstable gait, slow speech, and poor handwriting and died of density SNP markers. stroke at 59 years of age. Four siblings (II-4, II-5, II-7, and II-8) and an offspring of individual II-8 (III-1) are also affected. We examined other siblings (II-1, II-2, II-3, II-6, METHODS and II-9) and confirmed that they had no symptoms. Indi- vidual III-1 was not included in the genetic analysis because SUBJECTS informed consent was not obtained. A summary of clinical features is shown in the Table. The pedigree of this family is shown in modified form in Pure cerebellar ataxia with very slow progression is the com- Figure 1. The family resides in Hokkaido, the northern- mon feature in all 5 affected individuals. They had been in most island of Japan. Based on the information provided by good health, except for mild hypertension in one (II-5), the family members, their affected ancestor (I-1) had an until the onset of gait disturbance and/or speech difficulty at

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Individuals in Pedigree

Characteristic II-4 II-5 II-7 II-8 III-1 Age, y At examination 40 39 34 40 16 At symptom onset 35 35 28 38 13 Symptoms at onset Difficulty walking Difficulty walking, Difficulty walking Difficulty walking Head tremor poor handwriting SARA score (DD, y)a Not obtained 14.5 (26) 13.0 (28) 12.5 (26) 4.0 (5) Ocular overshoot Equivocal ϩϩ− ϩ Saccadic pursuit ϩϩ ϩϩ− Gaze nystagmus − − − − − Dysarthria ϩϩ ϩϩ− Reflexes Upper limb ϩϩϩ ϩϩ ϩϩ ϩϩ ϩϩ Lower limb ϩϩϩ ϩϩϩ ϩϩϩ ϩϩ ϩϩ Gait ataxia ϩϩ ϩϩϩ Ataxia Upper limb ϩϩ ϩϩϩ Lower limb ϩϩ ϩϩϩ Muscle tone Spasticity Normal Normal Normal Normal Involuntary movement − − − − Head tremor Neuropathy − − − − − Parkinsonism − − − − − Dementia − − − − − MRI findings CA CA, mild ischemic CA CA CA lesion in DWM Other complications − Hypertension MALT lymphoma −− of the duodenum CAG repeats in 16/17 16/17 16/17 16/17 Not obtained PPP2R2B gene

Abbreviations: CA, cerebellar atrophy; DD, disease duration; DWM, deep white matter; MALT, mucosa-associated lymphoid tissue; MRI, magnetic resonance imaging; SARA, Scale for the Assessment and Rating of Ataxia; ϩ, present; −, absent. a Higher SARA scores indicate greater severity of ataxia (maximum, 40 points).

13 to 38 years of age (mean age, 29.8 years). Two affected DNA SAMPLING AND EXCLUSION siblings (II-5 and II-7) needed cane assistance 22 and 23 OF KNOWN SCA GENOTYPES years, respectively, after the onset of symptoms. Other individuals (II-8 and III-1) can still walk without assistance. The All procedures used in this study were approved by the Hok- most recent mean total score on the Scale for the Assessment kaido University Ethics Committee. After written informed con- and Rating of Ataxia7 for these 3 individuals was 11, indicat- sent was obtained from each individual (I-2 and II-1 through ing mild to moderate disability. One affected family member II-9), blood samples were collected and genomic DNA was ex- (II-4) has not been examined since 1997 because of a change tracted from the leukocytes. Using methods described previ- in his place of residence. ously, we excluded abnormal expansion of CAG/CTG repeats Neurological examination of all affected members showed or reported mutations in each gene of SCA1, SCA2, Machado- limb and trunk ataxia. Only 1 family member (III-1) did not Joseph disease/SCA3, SCA5, SCA6, SCA7, SCA8, SCA10, den- have dysarthria (slurred speech) or defects of smooth pursuit. tatorubral-pallidoluysian atrophy, SCA12, SCA13, SCA14, The initial symptom of the other individuals (except for III-1) SCA17, and SCA27 in each individual.8 The C→T change in was gait disturbance and, for individual III-1, an involuntary the 5Ј untranslated region of the puratrophin 1 gene with link- movement (head tremor). Three individuals (II-4, II-5, and II-7) age disequilibrium for 16q22.1-linked ADCA was also exam- had brisk deep tendon reflexes in the lower limbs. Further- ined and excluded using previously described methods.9 more, one of these (II-4) had ankle clonus and equivocal spasticity without an extensor plantar reflex. None of the affected individuals had gaze-evoked nystagmus. At last follow-up, none GENOTYPING AND LINKAGE ANALYSIS of them showed obvious dementia, parkinsonism, neuropathy, or autonomic disturbance. One family member (II-7) de- After differentiating 14 SCAs, a genome-wide linkage analysis veloped duodenal lymphoma of the mucosa-associated lym- was performed in each of the family members (6 healthy and phoid tissue at 54 years of age and was successfully treated with 4 affected) using the genome-wide human SNP array (Af- radiation therapy. fymetrix, version 6.0; Hitachi, Ltd, Tokyo, Japan) containing All affected individuals underwent magnetic resonance 909 622 SNPs according to the manufacturer’s instructions.10 imaging, which showed atrophy of the cerebellum, including Parametric linkage analysis was performed using Allegro with the vermis and hemisphere, but no abnormalities of the brain- SNP HiTLink (a high-throughput linkage analysis system).11 stem or supratentorial structures except for mild ischemic le- The LOD scores were generated by assuming an equal sex re- sions in the deep white matter of individual II-5 (Figure 2). combination rate and an autosomal dominant disease locus with

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LOD Score 1

0 pter BC D E qter Chromosome 5

Figure 3. Logarithm of odds (LOD) scores plotted on chromosome 5. The theoretical maximum LOD score in this family was obtained on the E locus (LOD score, 2.408).

kb; 4.0 megabases; and 621, 406, and 623 kb, respectively, with LOD scores of 1.026, 0.633, 0.633, 1.032, 2.408, 2.214, 1.425, and 1.408, respectively. Because the LOD score of markers adjacent to those with almost posi- Figure 2. Midsagittal magnetic resonance image (MRI) (1.5 T; T1-weighted) of the brain of individual II-5 21 years after onset of autosomal dominant tive LOD scores had minus infinity in all loci except for cerebellar ataxia. The MRI study showed marked atrophy of the vermis and E and because double recombination in this narrow re- cerebellar hemispheres (not shown) without involvement of the brainstem or gion is extremely rare, it is likely that these 7 loci do not supratentorial structures. link with a disease locus in this family. The E locus on chromosome 5q had a multipoint LOD score of 2.408, a penetrance of 100% and a gene frequency of 0.001. Allele fre- the theoretical maximum that can be obtained in our fam- quencies were obtained by the analysis of 200 control sub- ily, and so was considered a candidate (Figure 3). jects. The SNP markers were selected on the basis of a Hardy- Using the pairwise LOD scores based on all SNP mark- Weinberg equilibrium of greater than 0.05, with a call rate of ers, the centromeric boundary of the candidate locus was 1 and a confidence score of less than 0.02. Markers for which determined to be between rs681591 and rs10477291, and the minor allele frequency was zero were eliminated. To avoid the teromeric boundary was between rs741580 and inaccuracies that can be accompanied by an inflated LOD score, the SNP with the highest minor allele frequency in the region rs32582 (Figure 1). The candidate locus maps to 5q31- between 80 and 120 kilobases (kb) was selected by the mini- q33.1, the location of the PPP2R2B gene. The candidate mum-maximum method.11 The chromosomes, including sug- locus in this ADCA is not associated with any of the known gested loci, were also analyzed by all markers using MLINK in SCA loci except for SCA12. linkage/FASTLINK.12,13 We excluded SCA12 in this family because we found no abnormal expansion of CAG repeats in the promoter DNA SEQUENCING region of their PPP2R2B gene (16 of 17 repeats in all affected members except for III-1; Table). Direct nucleo- On the basis of the linkage analysis results, direct nucleotide tide sequence analysis showed no mutations in the 9 ex- sequencing of candidate gene PPP2R2B (protein phosphatase ons, including the promoter region and the exon-intron 2, regulatory subunit B, beta isoform; OMIM *604325) was per- boundaries of this gene. formed. Nine exons—including 2 splice variants of exon 1,14 the promoter region, 500 bases upstream from the transcrip- tion initiation site, and the exon-intron boundaries of the COMMENT PPP2R2B gene in affected family members—were amplified using standard polymerase chain reaction methods. After treatment We describe herein a dominant cerebellar ataxia that maps with shrimp alkaline phosphatase and exonuclease I, the poly- to chromosome 5q and includes the SCA12 locus but merase chain reaction samples were directly sequenced (Prism without the pathogenic mutations in the promoter re- BigDye terminator, version 1.1, and 310 Genetic Analyzer; Ap- gion and exons of the PPP2R2B gene. plied BioSystems, Tokyo, Japan). Spinocerebellar ataxia 12 is caused by CAG trinucleo- tide repeat expansions in the promoter region of the RESULTS PPP2R2B gene (55-78 triplets in the mutant alleles and 7-32 in the normal ones).15-17 To date, SCA12 has been Multipoint linkage analysis by selected SNP markers iden- reported only in the people of German15 and Indian16-18 tified the following 8 loci on 4 chromosomes with a posi- descent but not yet in the Japanese population. Besides tive LOD score: 1 locus (called A) on chromosome 1, 4 expansion of CAG repeats, no other mutation has been (B, C, D, and E) on chromosome 5, 1 (F) on chromo- reported from such SCA12 families, to our knowledge. some 15, and 2 (G and H) on chromosome 17. All the Patients with SCA12 typically develop action tremors LOD scores of the remaining loci were less than −2.0. The of the arms or head in the fourth decade of life (100%), then size of the loci from A to H were 355, 597, 527, and 263 cerebellar ataxia, hyperreflexia, parkinsonism (80%), anxi-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 ety or depression (40%), and dementia (20%).19 How- ebellum.27 In contrast, ADRB2 shows expression in the ever, patients from India differ somewhat from other fami- cerebellum, with particularly increased expression in the lies with SCA12; they can develop facial myokymia (33%) glial cells of the cerebellum of patients with olivoponto- and subclinical sensory and motor neuropathy (33% to ap- cerebellar atrophy.28 However, there is no report about proximately 50%) but lack symptoms of dementia.16 The cerebellar ataxia as a phenotype of ADRB2 transgenic and severity of cerebellar ataxia of SCA12 is milder than that knockout mice, in which neuroprotection to ischemic in- of other dominant SCAs.19 Brain magnetic resonance juries and ineffectiveness of antidepressants against neu- imaging and computed tomography of patients with SCA12 ropathic pain have been shown.29,30 Therefore, these genes, show generalized atrophy in the cerebral cortex but less including ADRB2, should also be considered candidate so in the cerebellum.20 In contrast to these reports, the fam- genes along with PPP2R2B. Further study is needed to ily in the present study showed slowly progressive, al- investigate the region surrounding PPP2R2B, including most pure cerebellar ataxia without any signs of demen- introns and other genes in the candidate locus. Given that tia, neuropathy, autonomic failure, or parkinsonism, except the causative gene and responsible mutation have been for patient III-1, who had head tremor from the initial stage. identified in one family, these findings provide new in- Such involuntary movement has been described as the ma- sights into the pathogenesis of SCA12. jor symptom of patients with SCA12.19 Hyperreflexia was found in 3 patients (60%), a proportion similar to that ob- Accepted for Publication: January 18, 2010. served in SCA12. Nystagmus has been found in 30% of pa- Correspondence: Hidenao Sasaki, MD, PhD, Depart- tients with SCA12,19 but not in this family. Magnetic reso- ment of Neurology, Graduate School of Medicine, Hok- nance imaging showed atrophy that was restricted to the kaido University, N15 W7 Kita-ku, Sapporo 060-8638, cerebellum in our family. Japan ([email protected]). Despite several commonalities, the clinical differ- Author Contributions: Drs Sato, Yabe, and Sasaki had ences between SCA12 and the present family may indi- full access to all the data in the study and take respon- cate that these disorders have a different molecular patho- sibility for the integrity of the data and the accuracy of genesis. However, it is difficult to predict from the clinical the data analysis. Study concept and design: Tsuji and phenotype in this ADCA family whether the causative Sasaki. Acquisition of data: Sato, Yabe, Soma, Tsuji, and gene is different from PPP2R2B because of intrafamilial Sasaki. Analysis and interpretation of data: Sato, Yabe, and interfamilial variability and the phenotypic similar- Fukuda, Soma, Nakahara, Tsuji, and Sasaki. Drafting of ity seen in mutations of different genes in the SCAs.21,22 the manuscript: Sato, Yabe, Soma, Tsuji, and Sasaki. Criti- It may also be possible that SCA12 and our example of cal revision of the manuscript for important intellectual con- ADCA are allelic diseases, as has been observed in tent: Fukuda, Nakahara, and Tsuji. Statistical analysis: hemiplegic migraine, episodic ataxia type 2, and SCA6, Fukuda and Nakahara. Obtained funding: Sasaki. Admin- which are caused by different mutation patterns in the istrative, technical, and material support: Sato, Yabe, Soma, CACNA1A gene encoding the ␣1 subunit of the P/Q- Tsuji, and Sasaki. Study supervision: Tsuji and Sasaki. type voltage-gated calcium channel.23-25 Financial Disclosure: None reported. Because individual III-1 had a much earlier onset Funding/Support: This work was supported in part by than his father (II-8) and the other affected persons in a Grant-in-Aid from the Research Committee for Ataxic the family, the presence of anticipation, which is not Diseases, the Ministry of Health, Labour, and Welfare, obvious in SCA12,20 might be suspected. However, it is Japan. difficult to conclude this because of the small number of affected family members and the lack of genetic data REFERENCES for individual III-1. The PPP2R2B gene encodes a regulatory B subunit of 1. Matilla-Duen˜as A. The highly heterogeneous spinocerebellar ataxias: from genes protein phosphatase 2A (PP2A), which is a major class to targets for therapeutic intervention. Cerebellum. 2008;7(2):97-100. of serine/threonine phosphatases with essential func- 2. John S, Shephard N, Liu G, et al. 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