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Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia
Neurobiology of Aging 35 (2014) 1213.e13e1213.e17
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Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia Eun-Joo Kim a, Jay C. Kwon b, Kee Hyung Park c, Kyung-Won Park d, Jae-Hong Lee e, Seong Hye Choi f, Jee H. Jeong g, Byeong C. Kim h, Soo Jin Yoon i, Young Chul Yoon j, SangYun Kim k, Key-Chung Park l, Byung-Ok Choi m, Duk L. Na m, Chang-Seok Ki n, *, Seung Hyun Kim o, ** a Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Korea b Department of Neurology, Changwon Fatima Hospital, Changwon, Korea c Department of Neurology, Gachon University Gil Medical Center, Inchoen, Korea d Department of Neurology, Dong-A Medical Center, Dong-A University College of Medicine, Busan, Korea e Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea f Department of Neurology, Inha University School of Medicine, Incheon, Korea g Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea h Department of Neurology, Chonnam National University Medical School, Gwangju, Korea i Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea j Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea k Department of Neurology, Seoul National University College of Medicine and Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seoul, Korea l Department of Neurology, College of Medicine, Kyung Hee University, Seoul, Korea m Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea n Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea o Department of Neurology, Hanyang University College of Medicine, Seoul, Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 November 2013 Accepted 30 November 2013 Available online 4 December 2013
The hexanucleotide repeat expansion (GGGGCC) in chromosome 9 open-reading frame 72 (C9orf72) and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes are known to be associated with the main causes of familial or sporadic amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in Western populations. These genetic abnormalities have rarely been studied in Asian FTD populations. We investigated the frequencies of mutations in MAPT and GRN and the C9orf72 abnormal expansion in 75 Korean FTD patients. Two novel missense variants of unknown significance in the MAPT and GRN were detected in each gene. However, neither abnormal C9orf72 expansion nor pathogenic MAPT or GRN mutation was found. Our findings indicate that MAPT, GRN, and C9orf72 mutations are rare causes of FTD in Korean patients. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: C9orf72 Frontotemporal dementia GRN Korean MAPT Mutation
1. Introduction
* Corresponding author at: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul 135-710, Korea. Tel.: þ82 2 3410 2709; fax: þ82 2 3410 2719. ** Alternate corresponding author at: Department of Neurology, College of Medicine, Hanyang University, 17 Haengdan-dong, Seongdong-gu, Seoul, 133-791, Korea. Tel.: þ82 2 2290 8371; fax: þ82 2 2296 8370. E-mail addresses: [email protected] (C.-S. Ki), [email protected] (S. H. Kim). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.11.033
Frontotemporal dementia (FTD) is a presenile dementia syndrome characterized by impairment in behavior, language, and cognition associated with focal degeneration of the frontal and anterior temporal lobes. FTD consists of 3 subtypes: behavioral variant FTD (bvFTD) presenting with abnormal frontal behavioral symptoms and 2 language variants, semantic dementia (SD) with semantic anomia and progressive nonfluent aphasia (PNFA) with nonfluent and agrammatic speech (Neary et al., 1998). Up to 15% of
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patients with FTD have comorbid motor neuron disease (LomenHoerth et al., 2002). Nearly 40% of patients with FTD have a positive family history of dementia, and about 10% have an autosomal dominant pattern of inheritance (Rohrer et al., 2009). Seven genes have so far been recognized to cause familial FTD, including microtubule-associated protein tau (MAPT) (Hutton et al., 1998), progranulin (GRN) (Baker et al., 2006), valosin-containing protein (VCP) (Watts et al., 2004), chromatin-modifying protein 2B (CHMP2B) (Skibinski et al., 2005), TAR DNA-binding protein (TARDBP) (Benajiba et al., 2009), fused in sarcoma (FUS) (Van Langenhove et al., 2010), and chromosome 9 open-reading frame 72 (C9orf72) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). Of these, mutations in the MAPT and GRN genes are found in approximately 50% of the familial FTD cases and a recently identified C9orf72 hexanucleotide repeat expansion accounts for about 10%e30% of familial FTD (Seelaar et al., 2011; van Swieten and Grossman, 2012). In contrast, 4 other genes, VCP, CHMP2B, TARDBP, and FUS, are implicated in <5% of all FTD cases. Even though it is generally known that FTD has a strong genetic component, there may be geographic and ethnic differences in its prevalence. Most studies about familial FTD have been reported in North America and Europe, whereas the limited number of studies from Asia have suggested a much lower incidence of familial FTD (Ikeda et al., 2004; Kang et al., 2010; Ren et al., 2012). So far, only 1 Korean familial FTD has been reported (Kim et al., 2011). Thus, in this study, we screened MAPT, GRN, and C9orf72 hexanucleotide repeat expansions, which are considered to be the main genetic causes of FTD, in the Korean FTD population to investigate whether there are any differences in mutation frequencies between Western and Asian populations.
Sequencher software (version 4.10.1; Gene Codes, Ann Arbor, MI) and compared with the reference sequences for MAPT (NM_016835.4) or GRN (NM_002087.2) genes. To describe sequence variations, we followed the guidelines of the Human Genome Nomenclature Committee that “A” of the ATG translation start site was numbered þ1 for the DNA sequence and the first methionine was numbered þ1 for the protein sequence. Any novel variants were tested on 700 control chromosomes by sequencing. The C9orf72 repeat expansion was tested using a 2-step polymerase chain reaction protocol, as described previously (Jang et al., 2013). First, the number of hexanucleotide repeats was determined in all patients using the genotyping primers (chr9:27563580F and chr9:27563465R; DeJesus-Hernandez et al., 2011). Then patients found to have a homozygous pattern were further analyzed using the repeat-primed polymerase chain reaction method (Renton et al., 2011). Two samples from the NINDS repository (ND06769 and ND08544) were purchased from Coriell Cell Repositories (Camden, NJ) and tested for the purpose of quality control. 2.3. Bioinformatics analysis The functional consequences of the missense variants of unknown significance were predicted in silico using PolyPhen-2 (Adzhubei et al., 2010) and SIFT (Kumar et al., 2009) software. In PolyPhen-2, a mutation is classified as “probably damaging” if it has q probabilistic score >0.15; remaining variants are classified as benign. Using SIFT, scores ranging from 0 to 1 are obtained to represent the normalized probability that a particular amino acid substitution will be tolerated. SIFT predicts that substitutions with scores less than 0.05 are deleterious. 3. Results
2. Methods 3.1. Clinical findings 2.1. Patients Between October 2012 and May 2013, patients were prospectively recruited from 11 neurology clinics across Korea. All the patients enrolled in this study met the research criteria for FTD proposed by Knopman et al. (2008) and were subclassified into bvFTD, SD, and PNFA. Patients who had clinical and electrophysiological evidence of motor neuron disease (MND) were also enrolled as FTD-MND, regardless of the clinical subtype of FTD. This study has been conducted as part of the Clinical Research Center for Dementia of South KoreaeFrontotemporal dementia registry study. Thus, all participants were registered in the Clinical Research Center for Dementia of South KoreaeFrontotemporal dementia registry. The institutional review boards at all participating centers approved this study, and informed consent was obtained from patients and caregivers. 2.2. Genetic analysis Genomic DNA was extracted from peripheral blood leukocytes using the Wizard Genomic DNA Purification Kit following the manufacturer’s instructions (Promega, Madison, WI). All coding exons and their flanking introns of the MAPT and GRN genes were amplified using primer sets designed by the authors (available on request). The polymerase chain reaction was performed with a thermal cycler (model 9700; Applied Biosystems, Foster City, CA) as follows: 32 cycles of denaturation at 94 C for 30 seconds, annealing at 60 C for 30 seconds, and extension at 72 C for 30 seconds. After treatment of the amplicon (5 mL) with 10 U shrimp alkaline phosphatase and 2 U exonuclease I (USB Corp, Cleveland, OH), direct sequencing was performed with the BigDye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems) on an ABI Prism 3730xl genetic analyzer (Applied Biosystems). The obtained sequences were analyzed using
A total of 75 patients (42 men and 33 women) with FTD consisted of 22 bvFTD, 40 SD, 11 PNFA, and 2 FTD-MND patients. Two patients with FTD-MND showed abnormal behaviors as presenting symptoms. The mean age was 68.0 9.2 years, and mean age at onset was 63.3 9.7 years. The mean duration of follow-up was 5.0 3.6 years. Detailed demographic data of the 4 subtypes are summarized in Table 1. A history of dementia in first-degree relatives (parents and siblings) was found in 6.7% (5 of 75) of patients with FTD. 3.2. Genetic findings Sequencing of MAPT and GRN genes identified no known pathogenic mutation but only 2 novel missense variants of unknown significance in each gene: 1 was a heterozygous MAPT variant (c.530A > T; p.Asp177Val) and the other was a GRN variant (c.1138C > G; p.Gln380Glu). The MAPT p.Asp177Val variant was predicted to be possibly damaging by PolyPhen-2 but tolerated by SIFT, whereas the GRN p.Gln380Glu variant was predicted to be benign and tolerated by PolyPhen-2 and SIFT analysis, respectively (Table 2). However, neither variant was found in 700 control chromosomes. None of the patients had the C9orf72 repeat expansion (Table 3), whereas the expected sawtooth pattern with a 6-bp periodicity was observed in the 2 samples from the NINDS repository (data not shown). The most common allele was 2 hexanucleotide repeats (105 of 150; 70%), followed by 6 (19 of 150; 12.7%) and 8 repeats (12 of 150; 8%). 4. Discussion In our FTD population, no patient with the C9orf72 repeat expansion was detected. Because the C9orf72 hexanucleotide
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Table 1 Patients demographics
Number Age (y) Onset age (y) Sex (M:F) Disease duration (y) FTD-CDR (SB) K-MMSE
Total
bvFTD
SD
PNFA
FTD-MND
75 68.0 9.2 63.3 9.7 42:33 5.0 3.6 10.9 7.0 14.9 9.6
22 66.2 8.0 59.6 9.5 17:5 6.7 4.9 12.5 6.1 16.3 8.6
40 68.3 9.0 64.2 8.6 18:22 4.4 2.8 11.0 7.1 12.4 10.4
11 72.0 11.3 68.4 12.0 7:4 4.4 2.4 6.8 6.1 21.8 4.5
2 59.0 5.7 57.0 5.7 0:2 2.1 0.0 14.8 13.1 11.5 9.2
Key: BvFTD, behavioral variant FTD; CDR, Clinical Dementia Rating; F, female; M, male; MND, motor neuron disease; K-MMSE, Korean version of Mini-Mental State Examination; PNFA, progressive non-fluent aphasia; SB, sum of boxes; SD, semantic dementia.
(GGGGCC) repeat expansion was identified as the causative mutation in autosomal dominant familial FTD-amyotrophic lateral sclerosis (ALS) in 2011 (DeJesus-Hernandez et al., 2011; Renton et al., 2011), several population-based studies from Europe, North America, and Asia have suggested that there may be geographic or ethnic difference in the frequency of the repeat expansion in C9orf72 in sporadic ALS (sALS), familial ALS (fALS), sporadic FTD (sFTD), and familial FTD (fFTD) (Byrne et al., 2012; Chiò et al., 2012; Cooper-Knock et al., 2012; Daoud et al., 2012; DeJesus-Hernandez et al., 2011; Dobson-Stone et al., 2013; Englund et al., 2012; Ferrari et al., 2012; García-Redondo et al., 2013; Gijselinck et al., 2012; Ishiura et al., 2012; Jang et al., 2013; Konno et al., 2013; Majounie et al., 2012; Mok et al., 2012b; Ogaki et al., 2012; Renton et al., 2011; Sabatelli et al., 2012; Simón-Sánchez et al., 2012; Snowden et al., 2012; Stewart et al., 2012; Takada et al., 2012; Tsai et al., 2012; Zou et al., 2013). That is, the frequencies of the C9orf72 mutation ranged from 21% to 57% in fALS, 3% to 21% in sALS, and 12% to 29% in FTD in Western populations, whereas the frequencies ranged from 0% to 18.2% in fALS and 0.4% to 2% in sALS in Asian populations, with little available data of FTD (Majounie et al., 2012; Ogaki et al., 2012; Tsai et al., 2012). There has been only 1 report about the C9orf72 mutation in an Asian FTD population (Majounie et al., 2012), although a few studies have investigated C9orf72 frequency in Asian ALS populations, including Korea (Jang et al., 2013; Konno et al., 2013; Ogaki et al., 2012; Tsai et al., 2012; Zou et al., 2013). Majounie et al. searched for C9orf72 repeat expansion in only 10 Asian sFTD (9 bvFTD and 1 PNFA) and 3 Asian fFTD (3 bvFTD) patients and found it in 0% (0 of 10) of sFTD and 66.6% (2 of 3) of fFTD. Thus, our data may be the largest report of the C9orf72 mutation screening in an Asian FTD population, and no one with C9orf72 abnormal expansion was identified in this study. As noted earlier, because there has been no other investigation of the C9orf72 mutation in an Asian population other than the study by Majounie et al, and their number of subjects was very small, the comparisons that we can make between their study and ours are limited. However, 2 recently published studies of Korean and Chinese ALS populations showing negative results (Jang et al., 2013; Zou et al., 2013) and other studies of Japanese and Taiwanese ALS populations showed that the frequency of C9orf72 mutation ranged from 2% to 20% in sALS and fALS (Ishiura et al., 2012; Konno et al., 2013; Tsai
Table 2 Novel variants of unknown significance in GRN and MAPT genes Gene
Nucleotide change
Amino acid change
In silico analysis PolyPhen-2
SIFT
MAPT
c.530A > T
p.Asp177Val
Tolerated (0.34)
GRN
c.1138C > G
p.Gln380Glu
Possibly damaging (0.875) Benign (0.005)
Tolerated (0.20)
Key: GRN, progranulin; MAPT, microtubule-associated protein tau; Polyphen-2, polymorphism phenotyping 2; SIFT, sorting intolerant from tolerant.
et al., 2012), which may support previous reports suggesting that the C9orf72 pathogenic hexanucleotide repeat expansion might be derived from a single Northern European founder mutation (Mok et al., 2012a). This mutation may have entered Taiwan during the colonial rule of the Dutch and the Spanish in the 17th century and also penetrated into Japan during Japanese colonial rule in the 18th century (Tsai et al., 2012). Both MAPT and GRN genes are located on chromosome 17 and encode microtubule-associated protein tau and progranulin, respectively (Baker et al., 2006; Cruts et al., 2006; Wilhelmsen et al., 1994). Mutations of MAPT and GRN genes cause various clinical entities including FTD, primary progressive aphasia (PPA), progressive supranuclear palsy (PSP), corticobasal degeneration, and FTD with ALS (Boeve and Hutton, 2008). There have been 3 previous studies of the MAPT and GRN mutations in Asian population (Das et al., 2013; Kim et al., 2010; Ogaki et al., 2013). Kim et al. screened MAPT and GRN mutations in 45 Korean patients with PSP, CBS, or FTD and did not find any pathogenic mutations (Kim et al., 2010). They interpreted their negative results as being because of the small number of subjects, especially FTD patients (n ¼ 2), inclusion of sporadic cases only, and genetic ethnicity. Another study from Japan identified 5 MAPT mutations including 1 novel de novo mutation and 1 novel GRN mutation after direct sequence analysis in 75 patients with frontotemporal lobar degeneration (bvFTD, FTDALS, and PPA), PSP, and CBS. The number of FTD patients in their study was 38 (50.7%). However, all 5 patients with MAPT mutation were clinically diagnosed as early-onset PSP with the distinctive eye movement. One patient with the GRN mutation was associated with PPA (probably nonfluent type; Ogaki et al., 2013). Last, Das et al. screened 81 Indian patients with frontotemporal lobar degeneration (19 bvFTD, 3 SD, 4 PPA, 3 FTD-MND, 48 PSP, and 4 CBD) for mutation in MAPT and 33 of them for mutation in GRN (Das et al., 2013). They found 11 nucleotide variants in MAPT and 3 for GRN but no pathogenic mutation in either MAPT or GRN. The present study with a relatively large FTD sample also found only 2 novel variants, 1 each in the MAPT and GRN genes. Considering that it is uncertain whether these VUS are pathogenic, the
Table 3 Genotype and allele distributions of the C9orf72 repeat expansion in 75 Korean patients with frontotemporal dementia Genotype
N (%)
Allele
N (%)
2/2 2/4 2/6 2/7 2/8 6/7 6/9 8/8 8/13 Total
34 2 17 9 9 1 1 1 1 75
2 4 6 7 8 9 13
105 2 19 10 12 1 1
Total
150 (100%)
(45.3%) (2.7%) (22.7%) (12.0%) (12.0%) (1.3%) (1.3%) (1.3%) (1.3%) (100%)
(70.0%) (1.3%) (12.7%) (6.7%) (8.0%) (0.7%) (0.7%)
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frequency of mutations in these 2 genes is quite low in Korean patients with FTD. In conclusion, our study reconfirmed that C9orf72, MAPT, and GRN mutations are relatively rare in Asian FTD populations, and the underlying pathogenesis of the geographic and ethnic variations should be elucidated through further study. Disclosure statement The authors have no actual or potential conflicts of interest. Acknowledgements This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020), and a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120182). References Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., Kondrashov, A.S., Sunyaev, S.R., 2010. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248e249. 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Negative results
Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia Eun-Joo Kim a, Jay C. Kwon b, Kee Hyung Park c, Kyung-Won Park d, Jae-Hong Lee e, Seong Hye Choi f, Jee H. Jeong g, Byeong C. Kim h, Soo Jin Yoon i, Young Chul Yoon j, SangYun Kim k, Key-Chung Park l, Byung-Ok Choi m, Duk L. Na m, Chang-Seok Ki n, *, Seung Hyun Kim o, ** a Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Korea b Department of Neurology, Changwon Fatima Hospital, Changwon, Korea c Department of Neurology, Gachon University Gil Medical Center, Inchoen, Korea d Department of Neurology, Dong-A Medical Center, Dong-A University College of Medicine, Busan, Korea e Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea f Department of Neurology, Inha University School of Medicine, Incheon, Korea g Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea h Department of Neurology, Chonnam National University Medical School, Gwangju, Korea i Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea j Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea k Department of Neurology, Seoul National University College of Medicine and Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seoul, Korea l Department of Neurology, College of Medicine, Kyung Hee University, Seoul, Korea m Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea n Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea o Department of Neurology, Hanyang University College of Medicine, Seoul, Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 November 2013 Accepted 30 November 2013 Available online 4 December 2013
The hexanucleotide repeat expansion (GGGGCC) in chromosome 9 open-reading frame 72 (C9orf72) and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes are known to be associated with the main causes of familial or sporadic amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in Western populations. These genetic abnormalities have rarely been studied in Asian FTD populations. We investigated the frequencies of mutations in MAPT and GRN and the C9orf72 abnormal expansion in 75 Korean FTD patients. Two novel missense variants of unknown significance in the MAPT and GRN were detected in each gene. However, neither abnormal C9orf72 expansion nor pathogenic MAPT or GRN mutation was found. Our findings indicate that MAPT, GRN, and C9orf72 mutations are rare causes of FTD in Korean patients. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: C9orf72 Frontotemporal dementia GRN Korean MAPT Mutation
1. Introduction
* Corresponding author at: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul 135-710, Korea. Tel.: þ82 2 3410 2709; fax: þ82 2 3410 2719. ** Alternate corresponding author at: Department of Neurology, College of Medicine, Hanyang University, 17 Haengdan-dong, Seongdong-gu, Seoul, 133-791, Korea. Tel.: þ82 2 2290 8371; fax: þ82 2 2296 8370. E-mail addresses: [email protected] (C.-S. Ki), [email protected] (S. H. Kim). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.11.033
Frontotemporal dementia (FTD) is a presenile dementia syndrome characterized by impairment in behavior, language, and cognition associated with focal degeneration of the frontal and anterior temporal lobes. FTD consists of 3 subtypes: behavioral variant FTD (bvFTD) presenting with abnormal frontal behavioral symptoms and 2 language variants, semantic dementia (SD) with semantic anomia and progressive nonfluent aphasia (PNFA) with nonfluent and agrammatic speech (Neary et al., 1998). Up to 15% of
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patients with FTD have comorbid motor neuron disease (LomenHoerth et al., 2002). Nearly 40% of patients with FTD have a positive family history of dementia, and about 10% have an autosomal dominant pattern of inheritance (Rohrer et al., 2009). Seven genes have so far been recognized to cause familial FTD, including microtubule-associated protein tau (MAPT) (Hutton et al., 1998), progranulin (GRN) (Baker et al., 2006), valosin-containing protein (VCP) (Watts et al., 2004), chromatin-modifying protein 2B (CHMP2B) (Skibinski et al., 2005), TAR DNA-binding protein (TARDBP) (Benajiba et al., 2009), fused in sarcoma (FUS) (Van Langenhove et al., 2010), and chromosome 9 open-reading frame 72 (C9orf72) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). Of these, mutations in the MAPT and GRN genes are found in approximately 50% of the familial FTD cases and a recently identified C9orf72 hexanucleotide repeat expansion accounts for about 10%e30% of familial FTD (Seelaar et al., 2011; van Swieten and Grossman, 2012). In contrast, 4 other genes, VCP, CHMP2B, TARDBP, and FUS, are implicated in <5% of all FTD cases. Even though it is generally known that FTD has a strong genetic component, there may be geographic and ethnic differences in its prevalence. Most studies about familial FTD have been reported in North America and Europe, whereas the limited number of studies from Asia have suggested a much lower incidence of familial FTD (Ikeda et al., 2004; Kang et al., 2010; Ren et al., 2012). So far, only 1 Korean familial FTD has been reported (Kim et al., 2011). Thus, in this study, we screened MAPT, GRN, and C9orf72 hexanucleotide repeat expansions, which are considered to be the main genetic causes of FTD, in the Korean FTD population to investigate whether there are any differences in mutation frequencies between Western and Asian populations.
Sequencher software (version 4.10.1; Gene Codes, Ann Arbor, MI) and compared with the reference sequences for MAPT (NM_016835.4) or GRN (NM_002087.2) genes. To describe sequence variations, we followed the guidelines of the Human Genome Nomenclature Committee that “A” of the ATG translation start site was numbered þ1 for the DNA sequence and the first methionine was numbered þ1 for the protein sequence. Any novel variants were tested on 700 control chromosomes by sequencing. The C9orf72 repeat expansion was tested using a 2-step polymerase chain reaction protocol, as described previously (Jang et al., 2013). First, the number of hexanucleotide repeats was determined in all patients using the genotyping primers (chr9:27563580F and chr9:27563465R; DeJesus-Hernandez et al., 2011). Then patients found to have a homozygous pattern were further analyzed using the repeat-primed polymerase chain reaction method (Renton et al., 2011). Two samples from the NINDS repository (ND06769 and ND08544) were purchased from Coriell Cell Repositories (Camden, NJ) and tested for the purpose of quality control. 2.3. Bioinformatics analysis The functional consequences of the missense variants of unknown significance were predicted in silico using PolyPhen-2 (Adzhubei et al., 2010) and SIFT (Kumar et al., 2009) software. In PolyPhen-2, a mutation is classified as “probably damaging” if it has q probabilistic score >0.15; remaining variants are classified as benign. Using SIFT, scores ranging from 0 to 1 are obtained to represent the normalized probability that a particular amino acid substitution will be tolerated. SIFT predicts that substitutions with scores less than 0.05 are deleterious. 3. Results
2. Methods 3.1. Clinical findings 2.1. Patients Between October 2012 and May 2013, patients were prospectively recruited from 11 neurology clinics across Korea. All the patients enrolled in this study met the research criteria for FTD proposed by Knopman et al. (2008) and were subclassified into bvFTD, SD, and PNFA. Patients who had clinical and electrophysiological evidence of motor neuron disease (MND) were also enrolled as FTD-MND, regardless of the clinical subtype of FTD. This study has been conducted as part of the Clinical Research Center for Dementia of South KoreaeFrontotemporal dementia registry study. Thus, all participants were registered in the Clinical Research Center for Dementia of South KoreaeFrontotemporal dementia registry. The institutional review boards at all participating centers approved this study, and informed consent was obtained from patients and caregivers. 2.2. Genetic analysis Genomic DNA was extracted from peripheral blood leukocytes using the Wizard Genomic DNA Purification Kit following the manufacturer’s instructions (Promega, Madison, WI). All coding exons and their flanking introns of the MAPT and GRN genes were amplified using primer sets designed by the authors (available on request). The polymerase chain reaction was performed with a thermal cycler (model 9700; Applied Biosystems, Foster City, CA) as follows: 32 cycles of denaturation at 94 C for 30 seconds, annealing at 60 C for 30 seconds, and extension at 72 C for 30 seconds. After treatment of the amplicon (5 mL) with 10 U shrimp alkaline phosphatase and 2 U exonuclease I (USB Corp, Cleveland, OH), direct sequencing was performed with the BigDye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems) on an ABI Prism 3730xl genetic analyzer (Applied Biosystems). The obtained sequences were analyzed using
A total of 75 patients (42 men and 33 women) with FTD consisted of 22 bvFTD, 40 SD, 11 PNFA, and 2 FTD-MND patients. Two patients with FTD-MND showed abnormal behaviors as presenting symptoms. The mean age was 68.0 9.2 years, and mean age at onset was 63.3 9.7 years. The mean duration of follow-up was 5.0 3.6 years. Detailed demographic data of the 4 subtypes are summarized in Table 1. A history of dementia in first-degree relatives (parents and siblings) was found in 6.7% (5 of 75) of patients with FTD. 3.2. Genetic findings Sequencing of MAPT and GRN genes identified no known pathogenic mutation but only 2 novel missense variants of unknown significance in each gene: 1 was a heterozygous MAPT variant (c.530A > T; p.Asp177Val) and the other was a GRN variant (c.1138C > G; p.Gln380Glu). The MAPT p.Asp177Val variant was predicted to be possibly damaging by PolyPhen-2 but tolerated by SIFT, whereas the GRN p.Gln380Glu variant was predicted to be benign and tolerated by PolyPhen-2 and SIFT analysis, respectively (Table 2). However, neither variant was found in 700 control chromosomes. None of the patients had the C9orf72 repeat expansion (Table 3), whereas the expected sawtooth pattern with a 6-bp periodicity was observed in the 2 samples from the NINDS repository (data not shown). The most common allele was 2 hexanucleotide repeats (105 of 150; 70%), followed by 6 (19 of 150; 12.7%) and 8 repeats (12 of 150; 8%). 4. Discussion In our FTD population, no patient with the C9orf72 repeat expansion was detected. Because the C9orf72 hexanucleotide
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Table 1 Patients demographics
Number Age (y) Onset age (y) Sex (M:F) Disease duration (y) FTD-CDR (SB) K-MMSE
Total
bvFTD
SD
PNFA
FTD-MND
75 68.0 9.2 63.3 9.7 42:33 5.0 3.6 10.9 7.0 14.9 9.6
22 66.2 8.0 59.6 9.5 17:5 6.7 4.9 12.5 6.1 16.3 8.6
40 68.3 9.0 64.2 8.6 18:22 4.4 2.8 11.0 7.1 12.4 10.4
11 72.0 11.3 68.4 12.0 7:4 4.4 2.4 6.8 6.1 21.8 4.5
2 59.0 5.7 57.0 5.7 0:2 2.1 0.0 14.8 13.1 11.5 9.2
Key: BvFTD, behavioral variant FTD; CDR, Clinical Dementia Rating; F, female; M, male; MND, motor neuron disease; K-MMSE, Korean version of Mini-Mental State Examination; PNFA, progressive non-fluent aphasia; SB, sum of boxes; SD, semantic dementia.
(GGGGCC) repeat expansion was identified as the causative mutation in autosomal dominant familial FTD-amyotrophic lateral sclerosis (ALS) in 2011 (DeJesus-Hernandez et al., 2011; Renton et al., 2011), several population-based studies from Europe, North America, and Asia have suggested that there may be geographic or ethnic difference in the frequency of the repeat expansion in C9orf72 in sporadic ALS (sALS), familial ALS (fALS), sporadic FTD (sFTD), and familial FTD (fFTD) (Byrne et al., 2012; Chiò et al., 2012; Cooper-Knock et al., 2012; Daoud et al., 2012; DeJesus-Hernandez et al., 2011; Dobson-Stone et al., 2013; Englund et al., 2012; Ferrari et al., 2012; García-Redondo et al., 2013; Gijselinck et al., 2012; Ishiura et al., 2012; Jang et al., 2013; Konno et al., 2013; Majounie et al., 2012; Mok et al., 2012b; Ogaki et al., 2012; Renton et al., 2011; Sabatelli et al., 2012; Simón-Sánchez et al., 2012; Snowden et al., 2012; Stewart et al., 2012; Takada et al., 2012; Tsai et al., 2012; Zou et al., 2013). That is, the frequencies of the C9orf72 mutation ranged from 21% to 57% in fALS, 3% to 21% in sALS, and 12% to 29% in FTD in Western populations, whereas the frequencies ranged from 0% to 18.2% in fALS and 0.4% to 2% in sALS in Asian populations, with little available data of FTD (Majounie et al., 2012; Ogaki et al., 2012; Tsai et al., 2012). There has been only 1 report about the C9orf72 mutation in an Asian FTD population (Majounie et al., 2012), although a few studies have investigated C9orf72 frequency in Asian ALS populations, including Korea (Jang et al., 2013; Konno et al., 2013; Ogaki et al., 2012; Tsai et al., 2012; Zou et al., 2013). Majounie et al. searched for C9orf72 repeat expansion in only 10 Asian sFTD (9 bvFTD and 1 PNFA) and 3 Asian fFTD (3 bvFTD) patients and found it in 0% (0 of 10) of sFTD and 66.6% (2 of 3) of fFTD. Thus, our data may be the largest report of the C9orf72 mutation screening in an Asian FTD population, and no one with C9orf72 abnormal expansion was identified in this study. As noted earlier, because there has been no other investigation of the C9orf72 mutation in an Asian population other than the study by Majounie et al, and their number of subjects was very small, the comparisons that we can make between their study and ours are limited. However, 2 recently published studies of Korean and Chinese ALS populations showing negative results (Jang et al., 2013; Zou et al., 2013) and other studies of Japanese and Taiwanese ALS populations showed that the frequency of C9orf72 mutation ranged from 2% to 20% in sALS and fALS (Ishiura et al., 2012; Konno et al., 2013; Tsai
Table 2 Novel variants of unknown significance in GRN and MAPT genes Gene
Nucleotide change
Amino acid change
In silico analysis PolyPhen-2
SIFT
MAPT
c.530A > T
p.Asp177Val
Tolerated (0.34)
GRN
c.1138C > G
p.Gln380Glu
Possibly damaging (0.875) Benign (0.005)
Tolerated (0.20)
Key: GRN, progranulin; MAPT, microtubule-associated protein tau; Polyphen-2, polymorphism phenotyping 2; SIFT, sorting intolerant from tolerant.
et al., 2012), which may support previous reports suggesting that the C9orf72 pathogenic hexanucleotide repeat expansion might be derived from a single Northern European founder mutation (Mok et al., 2012a). This mutation may have entered Taiwan during the colonial rule of the Dutch and the Spanish in the 17th century and also penetrated into Japan during Japanese colonial rule in the 18th century (Tsai et al., 2012). Both MAPT and GRN genes are located on chromosome 17 and encode microtubule-associated protein tau and progranulin, respectively (Baker et al., 2006; Cruts et al., 2006; Wilhelmsen et al., 1994). Mutations of MAPT and GRN genes cause various clinical entities including FTD, primary progressive aphasia (PPA), progressive supranuclear palsy (PSP), corticobasal degeneration, and FTD with ALS (Boeve and Hutton, 2008). There have been 3 previous studies of the MAPT and GRN mutations in Asian population (Das et al., 2013; Kim et al., 2010; Ogaki et al., 2013). Kim et al. screened MAPT and GRN mutations in 45 Korean patients with PSP, CBS, or FTD and did not find any pathogenic mutations (Kim et al., 2010). They interpreted their negative results as being because of the small number of subjects, especially FTD patients (n ¼ 2), inclusion of sporadic cases only, and genetic ethnicity. Another study from Japan identified 5 MAPT mutations including 1 novel de novo mutation and 1 novel GRN mutation after direct sequence analysis in 75 patients with frontotemporal lobar degeneration (bvFTD, FTDALS, and PPA), PSP, and CBS. The number of FTD patients in their study was 38 (50.7%). However, all 5 patients with MAPT mutation were clinically diagnosed as early-onset PSP with the distinctive eye movement. One patient with the GRN mutation was associated with PPA (probably nonfluent type; Ogaki et al., 2013). Last, Das et al. screened 81 Indian patients with frontotemporal lobar degeneration (19 bvFTD, 3 SD, 4 PPA, 3 FTD-MND, 48 PSP, and 4 CBD) for mutation in MAPT and 33 of them for mutation in GRN (Das et al., 2013). They found 11 nucleotide variants in MAPT and 3 for GRN but no pathogenic mutation in either MAPT or GRN. The present study with a relatively large FTD sample also found only 2 novel variants, 1 each in the MAPT and GRN genes. Considering that it is uncertain whether these VUS are pathogenic, the
Table 3 Genotype and allele distributions of the C9orf72 repeat expansion in 75 Korean patients with frontotemporal dementia Genotype
N (%)
Allele
N (%)
2/2 2/4 2/6 2/7 2/8 6/7 6/9 8/8 8/13 Total
34 2 17 9 9 1 1 1 1 75
2 4 6 7 8 9 13
105 2 19 10 12 1 1
Total
150 (100%)
(45.3%) (2.7%) (22.7%) (12.0%) (12.0%) (1.3%) (1.3%) (1.3%) (1.3%) (100%)
(70.0%) (1.3%) (12.7%) (6.7%) (8.0%) (0.7%) (0.7%)
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