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RAPID COMMUNICATION
Progranulin Locus Deletion in Frontotemporal Dementia I. Gijselinck,1,3 J. van der Zee,1,3 S. Engelborghs,4,5 D. Goossens,2 K. Peeters,1,3 M. Mattheijssens,1,3 E. Corsmit,1,3 J. Del-Favero,2 P.P. De Deyn,4,5 C. Van Broeckhoven,1,3 and M. Cruts1,3 1
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium; 2Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium; 3Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; 4 Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; 5Memory Clinic, Division of Neurology, Middelheim General Hospital, Antwerpen, Belgium Communicated by Haig H. Kazazian, Jr. Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN r 2007 Wiley-Liss, Inc. mutation frequencies are underestimated. Hum Mutat 29(1), 53–58, 2008. KEY WORDS:
progranulin; PGRN; GRN; frontotemporal dementia; haploinsufficiency
INTRODUCTION Frontotemporal dementia (FTD; MIM] 600274) represents the most frequent type of dementia after Alzheimer’s disease (AD; MIM] 104300) in the group of patients with onset age below 65 years [McKhann et al., 2001; Forman et al., 2006]. FTD is clinically characterized by profound changes in behavior and personality, followed by cognitive impairment, and eventually leading to dementia as a result of the progressive degeneration of frontal and temporal brain regions [Neary et al., 1998; Ratnavalli et al., 2002; Rosso et al., 2003]. Positive family history is observed in up to 50% of FTD patients indicating a significant genetic component in the etiology of FTD [Stevens et al., 1998; Rosso et al., 2003]. In 10 to 43% of families, FTD was explained by mutations in the microtubule associated protein tau gene (MAPT; MIM] 157140) [Hutton et al., 1998; Poorkaj et al., 1998], causing pathological tau deposits in the brain [Rademakers et al., 2004]. Recently, we and others identified mutations in progranulin (PGRN; approved HUGO gene symbol GRN; MIM] 138945), located at 17q21, in familial FTD patients with tau-negative, ubiquitin-immunoreactive brain inclusions (FTDU-17) [Cruts et al., 2006; Baker et al., 2006]. To date, 45 PGRN mutations were identified sharing the same pathogenic mechanism, i.e., loss of functional PGRN, suggesting a haploinsufficiency mechanism (AD&FTD mutation database: www.molgen.ua.ac.be/FTDMutations). The loss of functional protein mainly results from nonsense-mediated decay (NMD) of mutant transcripts containr 2007 WILEY-LISS, INC.
ing premature termination codons due to nonsense or splice-site mutations, or small insertions/deletions [Cruts et al., 2006; Baker et al., 2006; Huey et al., 2006; Pickering-Brown et al., 2006; Boeve et al., 2006; Masellis et al., 2006; Gass et al., 2006; Benussi et al., 2006; Bronner et al., 2007; Mesulam et al., 2007; Le Ber et al., 2007; Llado et al., 2007; Behrens et al., 2007; Leverenz et al., 2007; Spina et al., 2007]. However, since all mutation screening studies were performed using genomic sequencing of exons and flanking intronic regions, complex mutations like whole gene deletions or other copy number variations would not be identified. The Supplementary Material referred to in this article can be accessed at http://www.interscience.wiley.com/jpages/1059 -7794/ suppmat. Received 21 June 2007; accepted revised manuscript 17 August 2007. Correspondence to: Marc Cruts, PhD, Neurodegenerative Brain Diseases Group,VIB-Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium. E-mail:
[email protected] Grant sponsors: Special Research Fund of the University of Antwerp Fund for Scienti¢c Research Flanders (FWO-F); Institute for Science and Technology^Flanders (IWT-F); Interuniversity Attraction Poles program (IUAP) P6/43 of the Belgian Science Policy O⁄ce; Stichting Alzheimer Onderzoek (SAO); Alzheimer’s Association USA (Zenith award). DOI 10.1002/humu.20651 Published online 11 December 2007 in Wiley InterScience (www. interscience.wiley.com).
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Here, we assessed the contribution of genomic PGRN deletions to the etiology of FTD in a series of 103 unrelated Belgian patients. MATERIALS AND METHODS Patients We analyzed a series of 103 Belgian patients with pure FTD diagnosed using a standard protocol and established clinical criteria [Neary et al., 1998; Engelborghs et al., 2003]. A total of 12 patients had a definite diagnosis of FTDU, two of dementia lacking distinctive histopathology (DLDH), and one of Pick’s disease. Previous mutation analyses identified a MAPT mutation in three patients, a PGRN null-mutation in 11 patients and a presenilin 1 mutation in the patient with Pick’s pathology [Cruts et al., 2006]. In the whole sample, mean onset age was 63.879.1 years (range 40–90 years); there were 50 females and 53 males and 43 patients had a positive family history with at least one first-degree relative affected. The local medical ethical committee of the University of Antwerp approved the research protocols for clinical, genetic and neuropathological studies. Multiplex Amplicon Quanti¢cation We screened the FTD series with the multiplex amplicon quantification (MAQ) technique [Suls et al., 2006; Sleegers et al., 2006], consisting of a multiplex PCR amplification of several fluorescently-labeled test and reference amplicons, followed by fragment analysis on an ABI 3730 DNA analyzer (Applied Biosystems, Foster City, CA). The assay contained six test amplicons located in and around PGRN (Fig. 1A) and seven reference amplicons located at randomly selected genomic positions outside the PGRN region and known copy number variations (CNVs). These 13 fragments were PCR-amplified in a
single reaction containing 20 ng genomic DNA. Peak areas of the test amplicons were normalized to these of the reference amplicons. Comparison of normalized peak areas between patient and control individuals resulted in a dosage quotient (DQ) for each test amplicon, calculated by the MAQ software (MAQs) package (www.vibgeneticservicefacility.be/MAQ.htm). DQ values below 0.75 were considered indicative of a deletion. Real-Time PCR Allele Quanti¢cation Copy number changes of PGRN were tested by real-time PCR allele quantification (qPCR) using SYBRs Green I assays on the ABI Prism 7900HT Sequence Detection System (Applied Biosystems). A PCR amplicon was designed for each PGRN exon using PrimerExpress Software (Applied Biosystems) and quantified against one reference amplicon in human ubiquitin C (hUBC) and human b2-microglobulin (hB2M) (Supplementary Table S1 for primer sequences; available online at http://www.interscience.wiley.com/jpages/1059-7794/suppmat). A total of 20 ng genomic DNA of patients and control individuals were amplified in duplicate using the universal amplification protocol (Applied Biosystems) as previously described [Sleegers et al., 2006] and DQs were calculated by comparing normalized quantities between patient and control individuals. We also designed a TaqMan probe in PGRN exon 11 to confirm SYBR Green results (see Supplementary Table S1 for probe sequence). Semiquantitative Duplex PCR Mapping Panel To map the deletion in more detail, we performed 94 semiquantitative duplex PCR assays of fragments in and around PGRN that were coamplified with an arbitrarily chosen reference fragment (see Supplementary Table S2 for primers). DQs were
PGRN dosage analysis using MAQ and qPCR. A: Schematic representation of the PGRN genomic region (GenBank AC003043.1). PGRN coding regions are indicated with dark gray boxes, noncoding regions with light gray boxes. MAQ test amplicons (amp 1 to amp 6) are indicated with black vertical lines. B: Dosage plots of qPCR analyses of FTD patient DR184.1. In the y-axis are DQ values.The gray area represents normal variation (DQ 5 0.8^1.2); DQ values below 0.75 (red line) are indicative for a deletion. (Left): MAQ analysis of the PGRN test amplicons indicated in the x-axis. Each DQ value represents the mean of DQs with standard error bars obtained by normalization for the reference amplicons. (Right): qPCR SYBR Green analysis for all 13 PGRN exons indicated in the x-axis. Each DQ value represents the mean of DQs with standard error bars obtained by normalization for hB2M and hUBC, measured in duplicate.
FIGURE 1.
Human Mutation DOI 10.1002/humu
HUMAN MUTATION 29(1), 53^58, 2008
calculated as the ratio of the normalized band intensities in the patient to a control individual. RESULTS AND DISCUSSION MAQ analysis of the 103 FTD patients revealed the presence of a heterozygous deletion in patient DR184.1 (Fig. 1B). DQ values of all six test amplicons were below 0.75, although only slightly for amplicon 1, suggesting a genomic deletion of PGRN including the 30 and possibly 50 flanking regions. Deletions were excluded in 267 Belgian healthy control individuals using the same MAQ assay. Subsequently we performed SYBR Green qPCR of PGRN exon 11 in the complete FTD sample as an independent screening test for genomic rearrangements. This analysis revealed one genomic deletion of all 13 exons in patient DR184.1, compatible with MAQ results (Fig. 1B). This deletion was further confirmed by a qPCR assay using a TaqMan probe designed in PGRN exon 11 (see Supplementary Table S1 for probe sequence) (data not shown). We used a semiquantitative duplex PCR mapping panel to fine map the deletion in patient DR184.1. Two distinct deletions were observed: one containing PGRN and one about 77 kb upstream of the PGRN deletion (Figs. 2 and 3). The PGRN-containing deletion was delineated to a maximal region of 74.3 kb. The centromeric breakpoint was mapped to a 19.4-kb region between
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fragments cen 14 and cen 15; the telomeric breakpoint to about 1 kb between fragments tel 2 and tel 3 (Figs. 2 and 3). Short tandem repeat (STR) marker D17S1860, located between cen 14 and cen 15, was heterozygous in patient DR184.1, further fine mapping the centromeric breakpoint region to 14.3 kb and resulting in a final maximal deleted region of 69.1 kb (Figs. 2 and 3). The breakpoint regions did not contain paralogous direct repeats, suggesting that nonallelic homologous recombination is not the mechanism that caused the deletion. Alternatively, nonhomologous end joining (NHEJ) [Shaw and Lupski, 2004] might be the underlying mechanism since the centromeric breakpoint region contained an increased density of interspersed repetitive elements (86%) of which 51% consisted of Alu sequences. Due to these repetitive sequences, it was impossible to further fine map this region. Detailed investigation of the breakpoint regions would be necessary to understand the mechanism underlying this genomic rearrangement. The second deletion was mapped to a region of maximal 62.9 kb (Figs. 2 and 3) and was located in a known CNV locus where BAC array–comparative genomic hybridization (array-CGH) previously showed the heterozygous deletion of a region contained within two overlapping BAC clones, RP11-756H11 and RP11-546M21 (Fig. 3), in 8 and 1 of 95 unrelated individuals of mixed ethnicity, respectively [Wong et al., 2007] (Database of Genomic Variants; http://projects.tcag.ca/variation), indicating the occurrence of
FIGURE 2. Fine mapping of PGRN deletion using a semiquantitative duplex PCR mapping panel. (Upper panel): Agarose gel (2%) of selected duplex PCRs in patient DR184.1 and a control individual.T: test fragment; R: reference fragment. (Lower panel): Bands were quanti¢ed on Kodak Imaging Station 440 (Eastman Kodak, Rochester, NY) and DQs were calculated as the ratio of the normalized band intensities in the patient to a control individual.The graph shows the DQ values obtained for each fragment, indicated in the xaxis. DQ values below 0.75 (red line) are indicative of a deletion. A genomic segment of chromosome 17q21 is shown below the graph with the position of the ampli¢ed test fragments indicated with vertical bars. Minimal deleted regions are indicated in red and the breakpoint regions in black. The position of STR marker D17S1860, used to map the centromeric breakpoint region of the PGRNcontaining deletion, is shown.
Human Mutation DOI 10.1002/humu
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Mapping of PGRN deletion. Map of the 17q21 genomic region showing the identi¢ed deletions, gene annotation, STR marker, location of BACs in the CNV locus and location of MAQ amplicons and fragments used in the semiquantitative duplex PCRs. The minimal deleted regions are shown in dark gray and the breakpoint regions in light gray.
FIGURE 3.
differently sized CNVs in this region. The two deletions in patient DR184.1 were located on the same chromosome, since an unaffected sibling, who shared one haplotype with the proband, did not carry any of the two deletions (Fig. 4). Patient DR184.1 had a disease onset age of 71 years and died after a disease course of 3 years. She presented with frontal symptoms, including stereotypic behavior, agitation, impatience, episodic anxiety, paraphasias, and word finding problems, indicating a progressive frontal syndrome. Neuropsychologic testing at age 73 years showed severe general cognitive deterioration. The patient had a Mini Mental State Examination (MMSE) score of 11/30 and a Middelheim Frontality Score (MFS) [De Deyn et al., Human Mutation DOI 10.1002/humu
FIGURE 4. Segregation analysis in Family DR184. Pedigree of family DR184.1 showing the segregation of 14 chromosome 17q21 microsatellite markers with allele lengths indicated in base pairs, the PGRN-containing deletion (PGRN del) and the deletion centromeric of PGRN (CNV).The black bar represents the disease haplotype, gray and white bars represent una¡ected chromosomes; inferred alleles are indicated between parentheses. For markers D17S934 and Chr17^16 phase could not be determined (alleles in gray). The arrowhead identi¢es the index patient. The disease status is indicated by ¢lled symbols (affected), open symbols (una¡ected), or question marks (disease status unknown). An asterisk denotes that DNA was available for genotyping.
2005] of 6/10. Brain CT scan showed diffuse cortical and subcortical atrophy, most prominently in the frontal lobes, and cerebellar atrophy. Brain single-photon emission computed tomography (SPECT) scan showed diastasis of frontal cortical activity and severe relative hypoperfusion at both frontal sides with extension to both parietal sides. Family history was not recorded.
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In summary, we identified a PGRN-containing genomic deletion in one FTD patient using three different methods. The maximal deleted region contained the complete PGRN gene and two additional known genes at the centromeric end of PGRN: RAP2 interacting protein 8 (RPIP8; approved HUGO gene symbol, RUNDC3A; MIM] 605448) and solute carrier family 25, member 39 (SLC25A39; MIM] 610820) (Fig. 3), of which one allele might be sufficient to execute normal function since the patient presented with typical FTD in the absence of additional symptoms. The deletion of PGRN on one allele results in the absence of mutant PGRN RNA demonstrating that haploinsufficiency is the sole mechanism of PGRN mutations necessary to initiate the disease process, in the absence of residual truncated or frameshift protein resulting from transcripts that escaped the cell’s control mechanisms, e.g. NMD. We extended the PGRN mutation spectrum of which genomic deletions explained 1% of the genetic etiology of FTD in the Belgian sample, underlining the importance of dosage mutation screening. Together with the previously described null mutations in 11 patients [Cruts et al., 2006], PGRN mutations account for 11.7% of all FTD patients. These frequencies might even be underestimated because whole gene deletions in low quality DNA samples and out-of-frame single exon deletions or duplications could have been missed in our analyses. ACKNOWLEDGMENTS We are grateful to the patients and family members for their kind cooperation in this study and to the personnel of the Flanders Institute for Biotechnology (VIB) Genetic Service Facility (www. vibgeneticservicefacility.be). This research was supported in part by a Zenith award of the Alzheimer’s Association USA (to C.V.B.). The FWO-F provided a PhD fellowship to I.G. and a postdoctoral fellowship to S.E. J.v.d.Z. is holder of a PhD fellowship of IWT-F, Belgium. REFERENCES Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. 2006. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919. Behrens MI, Mukherjee O, Tu PH, Liscic RM, Grinberg LT, Carter D, Paulsmeyer K, Taylor-Reinwald L, Gitcho M, Norton JB, Chakraverty S, Goate AM, Morris JC, Cairns NJ. 2007. Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitinpositive inclusions and progranulin mutation. Alzheimer Dis Assoc Disord 21:1–7. Benussi L, Binetti G, Sina E, Gigola L, Bettecken T, Meitinger T, Ghidoni R. 2006. A novel deletion in progranulin gene is associated with FTDP17 and CBS. Neurobiol Aging. Boeve BF, Baker M, Dickson DW, Parisi JE, Giannini C, Josephs KA, Hutton M, Pickering-Brown SM, Rademakers R, Tang-Wai D, Jack CR, Jr, Kantarci K, Shiung MM, Golde T, Smith GE, Geda YE, Knopman DS, Petersen RC. 2006. Frontotemporal dementia and parkinsonism associated with the IVS111G-4A mutation in progranulin: a clinicopathologic study. Brain 129:3103–3114. Bronner IF, Rizzu P, Seelaar H, van Mil SE, Anar B, Azmani A, Kaat LD, Rosso S, Heutink P, van Swieten JC. 2007. Progranulin mutations in Dutch familial frontotemporal lobar degeneration. Eur J Hum Genet 15:369–374. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C,
57
Peeters K, Sciot R, Santens P, de Pooter T, Mattheijssens M, Van den BM, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C. 2006. Null mutations in progranulin cause ubiquitinpositive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924. De Deyn PP, Engelborghs S, Saerens J, Goeman J, Marien P, Maertens K, Nagels G, Martin JJ, Pickut BA. 2005. The Middelheim Frontality Score: a behavioural assessment scale that discriminates frontotemporal dementia from Alzheimer’s disease. Int J Geriatr Psychiatry 20:70–79. Engelborghs S, Dermaut B, Goeman J, Saerens J, Marien P, Pickut BA, Van den BM, Serneels S, Cruts M, Van Broeckhoven C, De Deyn PP. 2003. Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects. J Neurol Neurosurg Psychiatry 74:1148–1151. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van D, V, Lee VM, Miller BL, Trojanowski JQ, Grossman M. 2006. Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, Graff-Radford N, Uitti R, Dickson D, Wszolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, Weintraub S, Mesulam M, White CL, III, Woodruff B, Caselli R, Hsiung GY, Feldman H, Knopman D, Hutton M, Rademakers R. 2006. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001. Huey ED, Grafman J, Wassermann EM, Pietrini P, Tierney MC, Ghetti B, Spina S, Baker M, Hutton M, Elder JW, Berger SL, Heflin KA, Hardy J, Momeni P. 2006. Characteristics of frontotemporal dementia patients with a Progranulin mutation. Ann Neurol 60:374–380. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. 1998. Association of missense and 50 -splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. Le Ber I, van der Zee J, Hannequin D, Gijselinck I, Campion D, Puel M, Laquerriere A, de Pooter T, Camuzat A, Van den BM, Dubois B, Sellal F, Lacomblez L, Vercelletto M, Thomas-Anterion C, Michel BF, Golfier V, Didic M, Salachas F, Duyckaerts C, Cruts M, Verpillat P, Van Broeckhoven C, Brice A. 2007. Progranulin null mutations in both sporadic and familial frontotemporal dementia. Hum Mutat 28:846–855. Leverenz JB, Yu CE, Montine TJ, Steinbart E, Bekris LM, Zabetian C, Kwong LK, Lee VM, Schellenberg GD, Bird TD. 2007. A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 130:1360–1374. Llado A, Sanchez-Valle R, Rene R, Ezquerra M, Rey MJ, Tolosa E, Ferrer I, Molinuevo JL. 2007. Late-onset frontotemporal dementia associated with a novel PGRN mutation. J Neural Transm 114:1051–1054. Masellis M, Momeni P, Meschino W, Heffner R, Jr, Elder J, Sato C, Liang Y, George-Hyslop P, Hardy J, Bilbao J, Black S, Rogaeva E. 2006. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 129:3115–3123. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. 2001. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 58:1803–1809. Mesulam M, Johnson N, Krefft TA, Gass JM, Cannon AD, Adamson JL, Bigio EH, Weintraub S, Dickson DW, Hutton ML, Graff-Radford NR. 2007. Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol 64:43–47. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. 1998. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554. Human Mutation DOI 10.1002/humu
58
HUMAN MUTATION 29(1), 53^58, 2008
Pickering-Brown SM, Baker M, Gass J, Boeve BF, Loy CT, Brooks WS, Mackenzie IR, Martins RN, Kwok JB, Halliday GM, Kril J, Schofield PR, Mann DM, Hutton M. 2006. Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 129:3124–3126. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. 1998. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825. Rademakers R, Cruts M, Van Broeckhoven C. 2004. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24:277–295. Ratnavalli E, Brayne C, Dawson K, Hodges JR. 2002. The prevalence of frontotemporal dementia. Neurology 58:1615–1621. Rosso SM, Donker KL, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC. 2003. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 126:2016–2022. Shaw CJ, Lupski JR. 2004. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 13(Spec No 1):R57–R64.
Human Mutation DOI 10.1002/humu
Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del Favero J, Cruts M, van Duijn CM, Van Broeckhoven C. 2006. APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129:2977–2983. Spina S, Murrell JR, Huey ED, Wassermann EM, Pietrini P, Baraibar MA, Barbeito AG, Troncoso JC, Vidal R, Ghetti B, Grafman J. 2007. Clinicopathologic features of frontotemporal dementia with progranulin sequence variation. Neurology 68:820–827. Stevens M, van Duijn CM, Kamphorst W, de Knijff P, Heutink P, van Gool WA, Scheltens P, Ravid R, Oostra BA, Niermeijer MF, van Swieten JC. 1998. Familial aggregation in frontotemporal dementia. Neurology 50:1541–1545. Suls A, Claeys KG, Goossens D, Harding B, Van Luijk R, Scheers S, Deprez L, Audenaert D, Van Dyck T, Beeckmans S, Smouts I, Ceulemans B, Lagae L, Buyse G, Barisic N, Misson JP, Wauters J, Del Favero J, De Jonghe P, Claes LR. 2006. Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients. Hum Mutat 27:914–920. Wong KK, deLeeuw RJ, Dosanjh NS, Kimm LR, Cheng Z, Horsman DE, MacAulay C, Ng RT, Brown CJ, Eichler EE, Lam WL. 2007. A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 80:91–104.
