- Email: [email protected]
Mutational analysis of TARDBP in Parkinson's disease
Neurobiology of Aging 34 (2013) 1517.e1e1517.e3
Contents lists available at SciVerse ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
Mutational analysis of TARDBP in Parkinson’s disease Marka van Blitterswijk a, Michael A. van Es a, Dagmar Verbaan b, c, Jacobus J. van Hilten c, Hans Scheffer d, Bart P. van de Warrenburg e, Jan H. Veldink a,1, Leonard H. van den Berg a, *,1 a
Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands c Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands d Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands e Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 August 2012 Received in revised form 10 September 2012 Accepted 11 September 2012 Available online 9 October 2012
Mutations in TAR DNA-binding protein (TARDBP) are associated with heterogenic phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson’s disease. In this study, we investigated the presence of TARDBP mutations in a cohort of 429 Dutch patients with Parkinson’s disease. Though we detected 1 silent mutation, p.S332S, no missense mutations were present in our cohort. Our findings, therefore, demonstrate that TARDBP mutations do not appear to contribute to the pathogenesis of Parkinson’s disease in The Netherlands. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Parkinson’s disease Amyotrophic lateral sclerosis TARDBP Genetics Mutation
1. Introduction Parkinson’s disease (PD) is an incurable neurodegenerative disorder, which causes a loss of dopaminergic cells in the substantia nigra of the midbrain. In patients of Sardinian descent with PD, mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), have recently been described (Quadri et al., 2011). A heterozygous p.A382T mutation was identified in 8 apparently unrelated patients with PD (2.5%). None of their first- or seconddegree relatives were affected by PD, dementia, or motor neuron disease (MND). Six of these patients displayed classical PD symptoms, and 2 presented with a postural instability or gait disturbance predominant type of PD, combined with mild cognitive impairment and psychotic phenomena (Quadri et al., 2011). Mutations in TARDBP were initially detected in patients with amyotrophic lateral sclerosis (ALS), the most frequent MND (Sreedharan et al., 2008). In Sardinia, the p.A382T mutation was identified in approximately 30% of the ALS patients, and originated
* Corresponding author at: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands. Tel.: þ31 88 7557939; fax: þ31 30 2542100. E-mail address: [email protected] (L.H. van den Berg). 1 Contributed equally. 0197-4580/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2012.09.013
from a common founder (Chio et al., 2011). Several of these ALS patients, however, developed extrapyramidal symptoms after their presentation with motor weakness. One Italian patient also developed a more complex neurological syndrome, consisting of ALS, parkinsonian features, motor and vocal tics, and frontotemporal dementia (FTD) (Borghero et al., 2011). In addition, Italian patients with p.A382T mutations were reported who developed FTD after the onset of ALS (Chio et al., 2010). Furthermore, 2 homozygous p.A382T mutations were found in a consanguineous Italian family: 1 family member presented with ALS, PD, and FTD, whereas the other was without neurologic complaints at time of publication (Mosca et al., 2012). In The Netherlands, we have shown that TARDBP mutations are present in 8.2% of the familial ALS families (van Blitterswijk et al., 2012). One mutation, p.N352S, accounted for more than half of these TARDBP mutations. Extended genealogical and haplotype analyses revealed a founder effect, similar to the p.A382T mutation in Sardinia. Because of the phenotypic variability that was observed in Sardinian patients with TARDBP mutations, we, therefore, investigated the presence of TARDBP mutations in patients with PD of Dutch descent. 2. Subjects, methods, and results The study population consisted of 429 patients with PD from The Netherlands. These patients were diagnosed, according to the
1517.e2
M. van Blitterswijk et al. / Neurobiology of Aging 34 (2013) 1517.e1e1517.e3
Table 1 Characteristics of the study population Diagnosis n PD
Male/female, Age at onset, Early/late, Positive/negative n (%) y (CI) n (%) family history, n (%)
429 280/149 (65/35)
51.9 (50.8e53.0)
204/225 (48/52)
141/280 (33/67)
Key: CI, 95% confidence interval; PD, Parkinson’s disease.
UK Brain Bank criteria (Hughes et al., 1992), and sampled at Leiden University Medical Center, and Radboud University Nijmegen Medical Center. Clinical characteristics of these patients are shown in Table 1. We used Sanger sequencing to screen exon 6 of TARDBP for mutations, as described previously (van Blitterswijk et al., 2012). To perform power calculations we used PS Power and Sample Size Calculation (version 3.0, http://biostat.mc.vanderbilt.edu/wiki/ Main/PowerSampleSize). This study had 97% power at an a of 0.05 to detect a mutation frequency of 2.5%, and 80% power to detect a frequency of 1.3%. In our cohort, we found 1 silent mutation (p.S332S); missense mutations were not identified. 3. Discussion Previously, screening of several PD cohorts also failed to identify patients with TARDBP mutations (Kabashi et al., 2009; Ticozzi et al., 2011). TARDBP mutations have, however, been detected in patients with a wide range of clinical phenotypes. For instance, TARDBP mutations (p.N267S, p.M359V) were identified in Italian patients with the behavioral variant of FTD without signs of MND (Borroni et al., 2009, 2010). In addition, a patient with a TARDBP mutation (p.K263E) has been described, who developed FTD, supranuclear palsy, and chorea (Kovacs et al., 2009). Moreover, in a cohort of French FTD-MND patients, 2 FTD-MND patients with TARDBP mutations (p.G295S) were discovered. One of these patients had the behavioral variant of FTD, the other patient had semantic dementia, and both these patients developed MND 2 years after the appearance of FTD symptoms (Benajiba et al., 2009). A patient with a TARDBP mutation (p.S393L) and a family history of ALS and parkinsonism was reported as well; this patient presented with progressive anarthria (Praline et al., 2012). Another case report described a patient with a TARDBP mutation (p.A382P) and a progressive severe sensory disorder, followed by a motor disorder, which evolved over 9 years, and showed mixed sensory and motor neuronopathy (Camdessanche et al., 2011). Furthermore, a TARDBP variant (p.A90V) has been detected in patients with both ALS and FTD, patients with ALS, and patients with Alzheimer’s disease; however, this mutation was also described in control subjects (Brouwers et al., 2010; Guerreiro et al., 2008; Kabashi et al., 2008; Kirby et al., 2010; Sreedharan et al., 2008; Winton et al., 2008). These findings highlight the genetic pleiotropy of TARDBP. Nonetheless, though TARDBP mutations are relatively common in Dutch ALS patients, our results demonstrate that they do not appear to be a cause of PD in The Netherlands. Disclosure statement The authors declare no actual or potential conflicts of interest exist. Patient material was obtained with approval of the Institutional Review Board, and participants provided informed consent. Acknowledgements This work was supported by the VSB fonds, Thierry Latran Foundation, Prinses Beatrix Fonds, Catharijne Stichting, H. Kersten
and M. Kersten, J. R. van Dijk, Adessium Foundation, and the Rudolf Magnus Young Talent Fellowship; the research leading to these results has received funding from the European Community’s Health Seventh Framework Program (FP7/2007-2013) under grant agreement n 259867. References Benajiba, L., Le Ber, I., Camuzat, A., Lacoste, M., Thomas-Anterion, C., Couratier, P., Legallic, S., Salachas, F., Hannequin, D., Decousus, M., Lacomblez, L., Guedj, E., Golfier, V., Camu, W., Dubois, B., Campion, D., Meininger, V., Brice, A., 2009. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann. Neurol. 65, 470e473. Borghero, G., Floris, G., Cannas, A., Marrosu, M.G., Murru, M.R., Costantino, E., Parish, L.D., Pugliatti, M., Ticca, A., Traynor, B.J., Calvo, A., Cammarosano, S., Moglia, C., Cistaro, A., Brunetti, M., Restagno, G., Chio, A., 2011. A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms, and FTD. Neurobiol. Aging 32, 2327.e1e2327.e5. Borroni, B., Archetti, S., Del Bo, R., Papetti, A., Buratti, E., Bonvicini, C., Agosti, C., Cosseddu, M., Turla, M., Di Lorenzo, D., Pietro Comi, G., Gennarelli, M., Padovani, A., 2010. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res. 13, 509e517. Borroni, B., Bonvicini, C., Alberici, A., Buratti, E., Agosti, C., Archetti, S., Papetti, A., Stuani, C., Di Luca, M., Gennarelli, M., Padovani, A., 2009. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum. Mutat. 30, E974eE983. Brouwers, N., Bettens, K., Gijselinck, I., Engelborghs, S., Pickut, B.A., Van Miegroet, H., Montoya, A.G., Mattheijssens, M., Peeters, K., De Deyn, P.P., Cruts, M., Sleegers, K., Van Broeckhoven, C., 2010. Contribution of TARDBP to Alzheimer’s disease genetic etiology. J. Alzheimers Dis. 21, 423e430. Camdessanche, J.P., Belzil, V.V., Jousserand, G., Rouleau, G.A., Creac’h, C., Convers, P., Antoine, J.C., 2011. Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation. Orphanet J. Rare Dis. 6, 4. Chio, A., Borghero, G., Pugliatti, M., Ticca, A., Calvo, A., Moglia, C., Mutani, R., Brunetti, M., Ossola, I., Marrosu, M.G., Murru, M.R., Floris, G., Cannas, A., Parish, L.D., Cossu, P., Abramzon, Y., Johnson, J.O., Nalls, M.A., Arepalli, S., Chong, S., Hernandez, D.G., Traynor, B.J., Restagno, G., 2011. Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene. Arch. Neurol. 68, 594e598. Chio, A., Calvo, A., Moglia, C., Restagno, G., Ossola, I., Brunetti, M., Montuschi, A., Cistaro, A., Ticca, A., Traynor, B.J., Schymick, J.C., Mutani, R., Marrosu, M.G., Murru, M.R., Borghero, G., 2010. Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations. Arch. Neurol. 67, 1002e1009. Guerreiro, R.J., Schymick, J.C., Crews, C., Singleton, A., Hardy, J., Traynor, B.J., 2008. TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS One 3, e2450. Hughes, A.J., Daniel, S.E., Kilford, L., Lees, A.J., 1992. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181e184. Kabashi, E., Daoud, H., Riviere, J.B., Valdmanis, P.N., Bourgouin, P., Provencher, P., Pourcher, E., Dion, P., Dupre, N., Rouleau, G.A., 2009. No TARDBP mutations in a French Canadian population of patients with Parkinson disease. Arch. Neurol. 66, 281e282. Kabashi, E., Valdmanis, P.N., Dion, P., Spiegelman, D., McConkey, B.J., Vande Velde, C., Bouchard, J.P., Lacomblez, L., Pochigaeva, K., Salachas, F., Pradat, P.F., Camu, W., Meininger, V., Dupre, N., Rouleau, G.A., 2008. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572e574. Kirby, J., Goodall, E.F., Smith, W., Highley, J.R., Masanzu, R., Hartley, J.A., Hibberd, R., Hollinger, H.C., Wharton, S.B., Morrison, K.E., Ince, P.G., McDermott, C.J., Shaw, P.J., 2010. Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis. Neurogenetics 11, 217e225. Kovacs, G.G., Murrell, J.R., Horvath, S., Haraszti, L., Majtenyi, K., Molnar, M.J., Budka, H., Ghetti, B., Spina, S., 2009. TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov. Disord. 24, 1843e1847. Mosca, L., Lunetta, C., Tarlarini, C., Avemaria, F., Maestri, E., Melazzini, M., Corbo, M., Penco, S., 2012. Wide phenotypic spectrum of the TARDBP gene: homozygosity of A382T mutation in a patient presenting with amyotrophic lateral sclerosis, Parkinson’s disease, and frontotemporal lobar degeneration, and in neurologically healthy subject. Neurobiol. Aging 33, 1846.e1e1846.e4. Praline, J., Vourc’h, P., Guennoc, A.M., Veyrat-Durebex, C., Corcia, P., 2012. Cooccurrence of progressive anarthria with an S393L TARDBP mutation and ALS within a family. Amyotroph. Lateral. Scler. 13, 155e157. Quadri, M., Cossu, G., Saddi, V., Simons, E.J., Murgia, D., Melis, M., Ticca, A., Oostra, B.A., Bonifati, V., 2011. Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson’s disease in Sardinia. Neurogenetics 12, 203e209.
M. van Blitterswijk et al. / Neurobiology of Aging 34 (2013) 1517.e1e1517.e3 Sreedharan, J., Blair, I.P., Tripathi, V.B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J.C., Williams, K.L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J.D., Leigh, P.N., Al-Chalabi, A., Miller, C.C., Nicholson, G., Shaw, C.E., 2008. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668e1672. Ticozzi, N., Leclerc, A.L., van Blitterswijk, M., Keagle, P., McKenna-Yasek, D.M., Sapp, P.C., Silani, V., Wills, A.M., Brown Jr., R.H., Landers, J.E., 2011. Mutational analysis of TARDBP in neurodegenerative diseases. Neurobiol. Aging 32, 2096e2099.
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van Blitterswijk, M., van Es, M.A., Hennekam, E.A., Dooijes, D., van Rheenen, W., Medic, J., Bourque, P.R., Schelhaas, H.J., van der Kooi, A.J., de Visser, M., de Bakker, P.I., Veldink, J.H., van den Berg, L.H., 2012. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 3776e3784. Winton, M.J., Van Deerlin, V.M., Kwong, L.K., Yuan, W., Wood, E.M., Yu, C.E., Schellenberg, G.D., Rademakers, R., Caselli, R., Karydas, A., Trojanowski, J.Q., Miller, B.L., Lee, V.M., 2008. A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Lett. 582, 2252e2256.
Contents lists available at SciVerse ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
Mutational analysis of TARDBP in Parkinson’s disease Marka van Blitterswijk a, Michael A. van Es a, Dagmar Verbaan b, c, Jacobus J. van Hilten c, Hans Scheffer d, Bart P. van de Warrenburg e, Jan H. Veldink a,1, Leonard H. van den Berg a, *,1 a
Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands c Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands d Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands e Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 August 2012 Received in revised form 10 September 2012 Accepted 11 September 2012 Available online 9 October 2012
Mutations in TAR DNA-binding protein (TARDBP) are associated with heterogenic phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson’s disease. In this study, we investigated the presence of TARDBP mutations in a cohort of 429 Dutch patients with Parkinson’s disease. Though we detected 1 silent mutation, p.S332S, no missense mutations were present in our cohort. Our findings, therefore, demonstrate that TARDBP mutations do not appear to contribute to the pathogenesis of Parkinson’s disease in The Netherlands. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Parkinson’s disease Amyotrophic lateral sclerosis TARDBP Genetics Mutation
1. Introduction Parkinson’s disease (PD) is an incurable neurodegenerative disorder, which causes a loss of dopaminergic cells in the substantia nigra of the midbrain. In patients of Sardinian descent with PD, mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), have recently been described (Quadri et al., 2011). A heterozygous p.A382T mutation was identified in 8 apparently unrelated patients with PD (2.5%). None of their first- or seconddegree relatives were affected by PD, dementia, or motor neuron disease (MND). Six of these patients displayed classical PD symptoms, and 2 presented with a postural instability or gait disturbance predominant type of PD, combined with mild cognitive impairment and psychotic phenomena (Quadri et al., 2011). Mutations in TARDBP were initially detected in patients with amyotrophic lateral sclerosis (ALS), the most frequent MND (Sreedharan et al., 2008). In Sardinia, the p.A382T mutation was identified in approximately 30% of the ALS patients, and originated
* Corresponding author at: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands. Tel.: þ31 88 7557939; fax: þ31 30 2542100. E-mail address: [email protected] (L.H. van den Berg). 1 Contributed equally. 0197-4580/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2012.09.013
from a common founder (Chio et al., 2011). Several of these ALS patients, however, developed extrapyramidal symptoms after their presentation with motor weakness. One Italian patient also developed a more complex neurological syndrome, consisting of ALS, parkinsonian features, motor and vocal tics, and frontotemporal dementia (FTD) (Borghero et al., 2011). In addition, Italian patients with p.A382T mutations were reported who developed FTD after the onset of ALS (Chio et al., 2010). Furthermore, 2 homozygous p.A382T mutations were found in a consanguineous Italian family: 1 family member presented with ALS, PD, and FTD, whereas the other was without neurologic complaints at time of publication (Mosca et al., 2012). In The Netherlands, we have shown that TARDBP mutations are present in 8.2% of the familial ALS families (van Blitterswijk et al., 2012). One mutation, p.N352S, accounted for more than half of these TARDBP mutations. Extended genealogical and haplotype analyses revealed a founder effect, similar to the p.A382T mutation in Sardinia. Because of the phenotypic variability that was observed in Sardinian patients with TARDBP mutations, we, therefore, investigated the presence of TARDBP mutations in patients with PD of Dutch descent. 2. Subjects, methods, and results The study population consisted of 429 patients with PD from The Netherlands. These patients were diagnosed, according to the
1517.e2
M. van Blitterswijk et al. / Neurobiology of Aging 34 (2013) 1517.e1e1517.e3
Table 1 Characteristics of the study population Diagnosis n PD
Male/female, Age at onset, Early/late, Positive/negative n (%) y (CI) n (%) family history, n (%)
429 280/149 (65/35)
51.9 (50.8e53.0)
204/225 (48/52)
141/280 (33/67)
Key: CI, 95% confidence interval; PD, Parkinson’s disease.
UK Brain Bank criteria (Hughes et al., 1992), and sampled at Leiden University Medical Center, and Radboud University Nijmegen Medical Center. Clinical characteristics of these patients are shown in Table 1. We used Sanger sequencing to screen exon 6 of TARDBP for mutations, as described previously (van Blitterswijk et al., 2012). To perform power calculations we used PS Power and Sample Size Calculation (version 3.0, http://biostat.mc.vanderbilt.edu/wiki/ Main/PowerSampleSize). This study had 97% power at an a of 0.05 to detect a mutation frequency of 2.5%, and 80% power to detect a frequency of 1.3%. In our cohort, we found 1 silent mutation (p.S332S); missense mutations were not identified. 3. Discussion Previously, screening of several PD cohorts also failed to identify patients with TARDBP mutations (Kabashi et al., 2009; Ticozzi et al., 2011). TARDBP mutations have, however, been detected in patients with a wide range of clinical phenotypes. For instance, TARDBP mutations (p.N267S, p.M359V) were identified in Italian patients with the behavioral variant of FTD without signs of MND (Borroni et al., 2009, 2010). In addition, a patient with a TARDBP mutation (p.K263E) has been described, who developed FTD, supranuclear palsy, and chorea (Kovacs et al., 2009). Moreover, in a cohort of French FTD-MND patients, 2 FTD-MND patients with TARDBP mutations (p.G295S) were discovered. One of these patients had the behavioral variant of FTD, the other patient had semantic dementia, and both these patients developed MND 2 years after the appearance of FTD symptoms (Benajiba et al., 2009). A patient with a TARDBP mutation (p.S393L) and a family history of ALS and parkinsonism was reported as well; this patient presented with progressive anarthria (Praline et al., 2012). Another case report described a patient with a TARDBP mutation (p.A382P) and a progressive severe sensory disorder, followed by a motor disorder, which evolved over 9 years, and showed mixed sensory and motor neuronopathy (Camdessanche et al., 2011). Furthermore, a TARDBP variant (p.A90V) has been detected in patients with both ALS and FTD, patients with ALS, and patients with Alzheimer’s disease; however, this mutation was also described in control subjects (Brouwers et al., 2010; Guerreiro et al., 2008; Kabashi et al., 2008; Kirby et al., 2010; Sreedharan et al., 2008; Winton et al., 2008). These findings highlight the genetic pleiotropy of TARDBP. Nonetheless, though TARDBP mutations are relatively common in Dutch ALS patients, our results demonstrate that they do not appear to be a cause of PD in The Netherlands. Disclosure statement The authors declare no actual or potential conflicts of interest exist. Patient material was obtained with approval of the Institutional Review Board, and participants provided informed consent. Acknowledgements This work was supported by the VSB fonds, Thierry Latran Foundation, Prinses Beatrix Fonds, Catharijne Stichting, H. Kersten
and M. Kersten, J. R. van Dijk, Adessium Foundation, and the Rudolf Magnus Young Talent Fellowship; the research leading to these results has received funding from the European Community’s Health Seventh Framework Program (FP7/2007-2013) under grant agreement n 259867. References Benajiba, L., Le Ber, I., Camuzat, A., Lacoste, M., Thomas-Anterion, C., Couratier, P., Legallic, S., Salachas, F., Hannequin, D., Decousus, M., Lacomblez, L., Guedj, E., Golfier, V., Camu, W., Dubois, B., Campion, D., Meininger, V., Brice, A., 2009. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann. Neurol. 65, 470e473. Borghero, G., Floris, G., Cannas, A., Marrosu, M.G., Murru, M.R., Costantino, E., Parish, L.D., Pugliatti, M., Ticca, A., Traynor, B.J., Calvo, A., Cammarosano, S., Moglia, C., Cistaro, A., Brunetti, M., Restagno, G., Chio, A., 2011. A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms, and FTD. Neurobiol. Aging 32, 2327.e1e2327.e5. Borroni, B., Archetti, S., Del Bo, R., Papetti, A., Buratti, E., Bonvicini, C., Agosti, C., Cosseddu, M., Turla, M., Di Lorenzo, D., Pietro Comi, G., Gennarelli, M., Padovani, A., 2010. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res. 13, 509e517. Borroni, B., Bonvicini, C., Alberici, A., Buratti, E., Agosti, C., Archetti, S., Papetti, A., Stuani, C., Di Luca, M., Gennarelli, M., Padovani, A., 2009. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum. Mutat. 30, E974eE983. Brouwers, N., Bettens, K., Gijselinck, I., Engelborghs, S., Pickut, B.A., Van Miegroet, H., Montoya, A.G., Mattheijssens, M., Peeters, K., De Deyn, P.P., Cruts, M., Sleegers, K., Van Broeckhoven, C., 2010. Contribution of TARDBP to Alzheimer’s disease genetic etiology. J. Alzheimers Dis. 21, 423e430. Camdessanche, J.P., Belzil, V.V., Jousserand, G., Rouleau, G.A., Creac’h, C., Convers, P., Antoine, J.C., 2011. Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation. Orphanet J. Rare Dis. 6, 4. Chio, A., Borghero, G., Pugliatti, M., Ticca, A., Calvo, A., Moglia, C., Mutani, R., Brunetti, M., Ossola, I., Marrosu, M.G., Murru, M.R., Floris, G., Cannas, A., Parish, L.D., Cossu, P., Abramzon, Y., Johnson, J.O., Nalls, M.A., Arepalli, S., Chong, S., Hernandez, D.G., Traynor, B.J., Restagno, G., 2011. Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene. Arch. Neurol. 68, 594e598. Chio, A., Calvo, A., Moglia, C., Restagno, G., Ossola, I., Brunetti, M., Montuschi, A., Cistaro, A., Ticca, A., Traynor, B.J., Schymick, J.C., Mutani, R., Marrosu, M.G., Murru, M.R., Borghero, G., 2010. Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations. Arch. Neurol. 67, 1002e1009. Guerreiro, R.J., Schymick, J.C., Crews, C., Singleton, A., Hardy, J., Traynor, B.J., 2008. TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS One 3, e2450. Hughes, A.J., Daniel, S.E., Kilford, L., Lees, A.J., 1992. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181e184. Kabashi, E., Daoud, H., Riviere, J.B., Valdmanis, P.N., Bourgouin, P., Provencher, P., Pourcher, E., Dion, P., Dupre, N., Rouleau, G.A., 2009. No TARDBP mutations in a French Canadian population of patients with Parkinson disease. Arch. Neurol. 66, 281e282. Kabashi, E., Valdmanis, P.N., Dion, P., Spiegelman, D., McConkey, B.J., Vande Velde, C., Bouchard, J.P., Lacomblez, L., Pochigaeva, K., Salachas, F., Pradat, P.F., Camu, W., Meininger, V., Dupre, N., Rouleau, G.A., 2008. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572e574. Kirby, J., Goodall, E.F., Smith, W., Highley, J.R., Masanzu, R., Hartley, J.A., Hibberd, R., Hollinger, H.C., Wharton, S.B., Morrison, K.E., Ince, P.G., McDermott, C.J., Shaw, P.J., 2010. Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis. Neurogenetics 11, 217e225. Kovacs, G.G., Murrell, J.R., Horvath, S., Haraszti, L., Majtenyi, K., Molnar, M.J., Budka, H., Ghetti, B., Spina, S., 2009. TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov. Disord. 24, 1843e1847. 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