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A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers

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A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers
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  1  A truncating mutation in  ATP13A2  is responsible for adult-onset neuronal ceroid 2  lipofuscinosis in Tibetan terriers 3  Fabiana H.G. Farias a , Rong Zeng a , Gary S. Johnson a, ⁎ , Fred A. Wininger b , Jeremy F. Taylor c , 4  Robert D. Schnabel c , Stephanie D. McKay c , Douglas N. Sanders d , Hannes Lohi e , Eija H. Seppälä e , 5  Claire M. Wade f ,1 , Kerstin Lindblad-Toh f ,g , Dennis P. O'Brien b , Martin L. Katz a,d 6  a Department of Veterinary Pathobiology, University of Missouri, Columbia, USA 7  b Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, USA 8  c Division of Animal Sciences, University of Missouri, Columbia, USA 9  d Mason Eye Institute, University of Missouri, Columbia, USA 10  e Departments of Veterinary Biosciences and Medical Genetics, Program in Molecular Medicine, University of Helsinki and Folkhälsan Research Center, Helsinki, Finland 11  f  Broad Institute of Harvard and MIT, Cambridge, MA, USA 12  g Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden 1314 a b s t r a c ta r t i c l e i n f o 15  Article history: 16  Received 7 October 2010 17  Revised 5 February 2011 18  Accepted 22 February 2011 19  Available online xxxx 20212223  Keywords: 24  ATP13A2 25  Kufs disease 26  PARK9 27  Kufor-Rakeb syndrome 28  Parkinson's disease 29  Dog 30  Neurodegeneration 31 A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide 32 association study restricted this NCL locus to a 1.3 Mb region of canine chromosome 2 which contains canine 33  ATP13A2 . NCL-affected dogs were homozygous for a single-base deletion in  ATP13A2 , predicted to produce a 34 frameshift and premature termination codon. Homozygous truncating mutations in human  ATP13A2  have 35 beenshownbyothers tocauseKufor-Rakebsyndrome(KRS), arareneurodegenerative disease.These fi nding 36 suggestthatKRSisalsoanNCL,althoughanalysisofKRSbraintissuewillbeneededtocon fi rmthisprediction. 37 Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with 38  ATP13A2  mutations; however, other clinical features differ between the species. For example, Tibetan terriers 39 with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and 40 pyramidal dysfunction not observed in affected Tibetan terriers. To see if   ATP13A2  mutations could be 41 responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced the  ATP13A2  from 28 42 Kufs disease patients. None of these patients had  ATP13A2  sequence variants likely to be causal for their 43 disease, suggesting that mutations in this gene are not common causes of Kufs disease. 44 © 2011 Published by Elsevier Inc. 4546474849  Introduction 50  The neuronal ceroid lipofuscinoses (NCLs) are a group of  51  progressive, neurodegenerative diseases characterized by the accu- 52  mulation of a variety of auto fl uorescent proteinaceous materials 53  within lysosomes in the brain, retina and other tissues. Homozygous 54  mutations which severely curtail the function of at least eight 55  different human genes have been reported to cause NCLs in infants 56  and children ( Jalanko and Braulke, 2009). Other mutations in some of  57 these same genes produce proteins with residual biological activities, 58 which can delay the onset of clinical signs until adulthood (van 59 Diggelen et al., 2001). The genetic etiologies are as yet unknown for a 60 second diverse set of adult-onset NCLs collectively referred to as Kufs 61 disease. 62 NCLs have been found or induced in a variety of domestic and 63 laboratory animals ( Jalanko and Braulke, 2009; Jolly, 1995; Katz et al., 64 2001). Mutations in  CLN1 ,  CLN2 ,  CLN5  and  CLN8  cause early-onset 65 canine NCLs (Awano et al., 2006a; Katz et al., 2005a; Melville et al., 66 2005; Sanders et al., 2010). Adult-onset NCL families have been 67 reported in several dog breeds (Alroy et al., 1992; Evans et al., 2005; 68 Narfstrom et al., 2007; Riis et al., 1992; Siso et al., 2004). The adult 69 onset NCL of American Bulldogs is caused by a mutation in  CTSD  (also 70 known as  CLN10 ) which encodes cathepsin D with residual protease 71 activity (Awano et al., 2006b). The recent discovery of an  ARSG 72 mutation in American Staffordshire terriers with adult-onset NCL has 73 resulted in the nomination of human  ARSG  as a potential Kufs disease Neurobiology of Disease xxx (2011) xxx – xxx ⁎  Corresponding author at: 322 Connaway Hall, University of Missouri, Columbia,Missouri, 65211, USA. Fax: +1 573 884 5414. E-mail address:  johnsongs@missouri.edu (G.S. Johnson). 1 New af  fi liation: Faculty of Veterinary Science, The University of Sydney, New SouthWales, Australia.  Available online on ScienceDirect (www.sciencedirect.com). YNBDI-02364; No. of pages: 7; 4C: 0969-9961/$  –  see front matter © 2011 Published by Elsevier Inc.doi:10.1016/j.nbd.2011.02.009 Contents lists available at ScienceDirect Neurobiology of Disease  journal homepage: www.elsevier.com/locate/ynbdi Please cite this article as: Farias, F.H.G., et al., A truncating mutation in  ATP13A2  is responsible for adult-onset neuronal ceroid lipofuscinosisin Tibetan terriers, Neurobiol. Dis. (2011), doi:10.1016/j.nbd.2011.02.009  74  locus (Abitbol et al., 2010). The disease in American Staffordshire 75  terriers differs from most other NCLs in that the auto fl uorescent 76  inclusionswerefoundprimarilyin the thalamus andcerebellum(Siso 77  et al., 2004); whereas, the auto fl uorescent inclusions are typically 78  distributed throughout the brain in Kufs disease and other types of  79  NCL (Berkovic et al., 1988; Jalanko and Braulke, 2009). A wide-spread 80  distribution of auto fl uorescent inclusions occurs in the brains of  81  Tibetan terriers with adult-onset NCL (Alroy et al., 1992; Katz et al., 82  2005b; Katz et al., 2007; Riis et al., 1992) and this disease has been 83  proposed to be a Kufs disease model (Abitbol et al., 2010; Katz et al., 84  2005b, 2007; Riis et al., 1992; Shibuya et al., 1998). 85  ATP13A2  is a member of the superfamily of P-type ATPase genes 86  which encode a wide variety of ion pumps (Thever and Saier, 2009). 87  Here we describe experiments indicating that homozygosity for a 88  truncating mutation in  ATP13A2  causes adult-onset NCL in Tibetan 89  terriers. Homozygous truncating mutations in human  ATP13A2  cause 90  Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease not 91  currentlyrecognizedasanNCL(Ramirezetal.,2006).TheKRSlocusis 92  also known as  PARK9  because  L  -dopa responsive parkinsonism is a 93  prominent early clinical feature of KRS (Lees and Singleton, 2007); 94  however, Tibetan terriers with NCL do not show signs of parkinson- 95  ism.Theclinicalfeaturesofthehumanandcanine  ATP13A2 -de fi ciency 96  diseases are compared in this report. Also reported are the results 97  from the resequencing of   ATP13A2  from 28 Kufs disease patients. 98  Materials and methods 99  Previously described methods were used to isolate DNA from 439 100  Tibetan terriers (Katz et al., 2005a). For 57 of these dogs, a 101  presumptive diagnosis of NCL was based on the owner's responses 102  to a questionnaire about abnormal behavioral signs (Katz et al., 103  2005b). Thirty-six of the Tibetan terriers with a presumptive 104  diagnosis of NCL were euthanized at the owner's request and tissues 105  from the brains and eyes were prepared for electron and fl uorescence 106  microscopy as previously described (Awano et al., 2006a). DNA 107  samplesfromhumanKufsdiseasepatientswereprovidedbyDr.Sarah 108  Mole of the MRC Laboratory for Molecular Cell Biology, Dr. Katherine 109  Sims of Harvard Medical School, and by the Human Brain and Spinal 110  Fluid Resource Center at the West Los Angeles VA Medical Center. 111  MRIs were obtained with a 1.5T GE Signa scanner. T2 weighted, 112  T2-FLAIR, T2*, 3-D T1 volumetric, and T1-weighted pre- and post- 113  intravenous gadolinium sequences were acquired in multiple planes. 114  A genome-wide association study (GWAS) was performed with 115  the Affymetrix Canine Genome 2.0 Array. Associations between the 116  disease phenotype and marker loci were determined under a 117  recessive model of inheritance as previously described (Farias et al., 118  2010). The PCR-ampli fi ed coding regions and intron – exon junctions 119  of canine and human  ATP13A2  were resequenced as previously 120  described (Farias et al., 2010). The sequences of the primers used to 121  amplify individual  ATP13A2  exons are provided in Supplementary 122  TablesS1(canine)andS2(human).Because  ATP13A2 isnotannotated 123  in build 2.1 of the NCBI canine genome reference sequence assembly, 124  we identi fi ed the 29 coding exons by discontinuous megablast query 125  of the reference sequence with individual bovine  ATP13A2  exon 126  sequences from GenBank accession NM_001192271 and by sequenc- 127  ingacrossagapinthecaninereferencesequenceassemblytoproduce 128  GenBank accession HQ224574 which contains the sequence for exon 129  23. These were assembled into a model cDNA sequence and a 130  predicted primary amino acid sequence (Supplementary Fig. S1), 131  which serve as bases for the canine cDNA and amino acid numbering 132  usedin this report.Thehuman  ATP13A2 -relatedcDNAandaminoacid 133  sequences were numbered as in GenBank accession NM_022089.2. 134  IndividualcanineDNAsamplesweregenotypedat  ATP13A2:c.1,623 by 135  PCR-RFLP with PCR primers 5 ′ -CCCGGGACTCATCACTGGC-3 ′  and 5 ′ - 136  GCTCGGCCTCCTCACCCAG-3 ′  which produced a 261 bp amplicon. The 137  ancestral allele was hydrolyzed by restriction enzyme  Bgl I into 138 fragments of 135 and 126 bp; whereas, the mutant allele lacked the 139 Bgl I restriction site. 140 Results 141 Of the 439 Tibetan terriers represented in our DNA collection, 57 142 exhibited behavioral changes and ataxia consistent with NCL. 143 Cerebral, cerebellar and occular tissue samples were collected at 144 necropsy from 36 of these potentially affected dogs. The presence of  145 auto fl uorescent cytoplasmic inclusions in 33 of these samples 146 con fi rmed the diagnosis of NCL (Fig. 1) and excluded NCL as the 147 cause of the neurological signs in the remaining 3 dogs. Electron 148 microscopy revealed the presence of membrane-bound inclusions 149 containing mixtures with varied ultrastructure (Fig. 2). A brain tumor 150 was identi fi ed in one dog without auto fl uorescent cytoplasmic 151 inclusions. The causes of neurological disease in the other two dogs 152 were not apparent. 153 A GWAS with DNA from 19 con fi rmed Tibetan terrier NCL cases 154 and 15 Tibetan terrier controls produced the strongest association 155 betweentheNCLphenotypeandSNPmarkersoncaninechromosome 156 2 (Fig. 3). Inspectionof the chromosome 2 genotypesrevealedthat all 157 19affecteddogswerehomozygousforthesame22-markerhaplotype 158 from  rs22857305  at 83,765,090 bp to  rs22859389  at 84,719,368 bp, 159 while none of the control dogs were homozygous for this haplotype. 160 Four affected dogswere heterozygous at centromeric fl ankingmarker 161 rs9159936   at 83,436,647 bp and three affected dogs were heterozy- 162 gous at telomeric  fl anking marker  rs9071523  at 84,736,776 bp. These 163 markers restricted the Tibetan terrier NCL locus to a 1.3 Mb region 164 which contained 18 genes including  ATP13A2 . DNA samples from two 165 NCL-affected and two normal Tibetan terriers were used to rese- 166 quence the coding regions and intron – exon junctions of all 29 coding 167 exons of   ATP13A2 . Comparison of DNA sequences from normal and 168 affected dogs revealed that the affected dogs had a single-base 169 deletion in exon 16,  ATP13A2:c.1,623delG , which predicted a frame 170 shift and premature termination codon (p.P541fsX597). 171 We genotyped all 439Tibetanterrier samples inour DNA collection 172 at  ATP13A2:c.1,623  by PCR-RFLP (Table 1). All 33 of the Tibetan terriers 173 with histopathologically con fi rmed NCL tested homozygous for the 174 deletion allele. Behavioral changes in these dogs were  fi rst noticed by 175 their owners at ages ranging from 4 to 9 years of age (mean 6.4 years). 176 No brain tissue samples were available to make de fi nitive diagnoses in 177 21 Tibetan terriers that exhibited the behavioral signs characteristic of  178 NCL and 16 of these dogs were homozygous for the deletion allele. The 179 remaining 5 dogs with behavioral changes plus the 3 dogs that lacked 180 auto fl uorescent inclusions represent only 2.1% (8/382) of the Tibetan 181 terriers that were not deletion-allele homozygotes, suggesting that 182 causesforNCL-likebehavioralchangesunrelatedto  ATP13A2 arerarein 183 the breed. All eight of the clinically normal dogs that tested 184 homozygous for the deletion allele were younger than 6 years old 185 whentheirhealthstatuswaslastreported(range1to5 yearsold,mean 186 2.3 years old) and were probably preclinical. None of the 140 clinically 187 normal Tibetan terriers that were 10 years old or older were 188 homozygous for the deletion allele. The distribution of genotypes in 189 thisgroupwassigni fi cantlydifferentthanthatofthe33NCL-con fi rmed 190 Tibetan terriers that were all homozygous for the deletion allele 191 (p=3.2×10 − 36 , Fischer's exact test 2×2). 192 Magnetic resonance images of the brain of a 9-year-old Tibetan 193 terrier that was homozygous for the deletion allele and exhibited 194 clinical signs of NCL revealed diffuse sulcal widening and global 195 dilation of the ventricles (Fig. 4A). The grey – white matter junction 196 was normal with no signal changes or contrast enhancement. These 197 fi ndings were most suggestive of diffuse brain atrophy, with no 198 speci fi c regional pyramidal changes. T2*-weighted images revealed 199 no signal changes indicative of iron deposition (Fig. 4B). Upon 200 necropsy,thisdogwascon fi rmedbyhistopathologicalexaminationto 201 have suffered from NCL. 2  F.H.G. Farias et al. / Neurobiology of Disease xxx (2011) xxx –  xxx Please cite this article as: Farias, F.H.G., et al., A truncating mutation in  ATP13A2  is responsible for adult-onset neuronal ceroid lipofuscinosisin Tibetan terriers, Neurobiol. Dis. (2011), doi:10.1016/j.nbd.2011.02.009  Fig. 1.  Fluorescence micrographs of cryostat sections of: (A) the cerebral cortex, (B) cerebellum, including the molecular layer (m), Purkinje layer (p), and granular layer (g);(C) retina; and, (D) optic nerve from a Tibetan terrier with NCL. Yellow-light-emitting auto fl uorescent storage material was abundant in all four tissues. In the retina, storagematerial with similar  fl uorescence properties accumulates normally in the retinal pigment epithelium during aging (arrowheads in C), but the auto fl uorescence in ganglion cells(arrowsinC)isspeci fi ctoNCL.BarinDindicatesmagni fi cationofallmicrographs.(Forinterpretationofthereferences tocolorinthis fi gurelegend,thereaderisreferredtothewebversion of this article.) Fig. 2.  Electron micrographs of storage bodies in neurons from the cerebral cortex of a Tibetan terrier affected with NCL. The storage body contents can be seen to be heterogeneousat the ultrastructural level. The storage bodies had membrane-like components (m), lipid-like components (l) and granular contents (g), sometimes all within the same storagebody (B).3 F.H.G. Farias et al. / Neurobiology of Disease xxx (2011) xxx –  xxx Please cite this article as: Farias, F.H.G., et al., A truncating mutation in  ATP13A2  is responsible for adult-onset neuronal ceroid lipofuscinosisin Tibetan terriers, Neurobiol. Dis. (2011), doi:10.1016/j.nbd.2011.02.009  202  Nine human  ATP13A2  sequence variants were found in DNA from 203  28 Kufs disease patients (Table 2). These included 7 synonymous 204  variants already reported in dbSNP (Phillips, 2007) and two novel 205  heterozygous variants:  c.A3414G , a synonymous variant detected in 206  one Kufs disease patient, and  c.G491A , a missense mutation which 207  predicted an amino acid substitution, p.R164Q, in a different Kufs 208  disease patient. 209  Discussion 210  Homozygous or compound heterozygous mutations in human 211  ATP13A2  can cause KRS (Ramirez et al., 2006). To date, only 16 KRS 212  patients and 8  ATP13A2  KRS-causing mutations have been described 213  (Crosiers et al., 2010; Di Fonzo et al., 2007; Ning et al., 2008; Paisán- 214  Ruiz et al., 2010; Ramirez et al., 2006; Santoro et al., 2010). Most of  215  thesepatientshadanapparentlyhealthyearlychildhoodandbeganto 216  show signs of disease between 10 and 22 years of age. Typically, signs 217  of parkinsonism including bradykinesia, rigidity, and hypomimia 218  were the predominant early clinical features. As the disease 219  progressed, additional symptoms appeared including supranuclear 220  gaze palsy, dystonia, amyotrophy, cognitive impairment, visual and 221  audio hallucinations, dementia, insomnia, mini-myoclonus, and 222  pyramidal signs including lower limb paresis, spasticity, hyper- 223  re fl exia and Babinski signs (Behrens et al., 2010; Di Fonzo et al., 224  2007; Najim al-Din et al., 1994; Ning et al., 2008; Paisán-Ruiz et al., 225  2010; Santoro et al., 2010; Schneider et al., 2010; Williams et al., 226  2005). An atypically mild disease phenotype was observed in a 31- 227  year-old patient diagnosed with mild mental retardation. Slight gaze 228  paresis, subtle pyramidal and extra-pyramidal signs, and moderate 229  generalized brain atrophy were detected when this patient was 230  carefully evaluated because he shared a homozygous  ATP13A2 231 missense mutation with his brother who exhibited the typical severe 232 KRS phenotype (Santoro et al., 2010). 233 Computed tomography scans or MRIs from KRS patients were 234 indicative of progressive generalized brain atrophy (Behrens et al., 235 2010; Di Fonzo et al., 2007; Najim al-Din et al., 1994; Santoro et al., 236 2010; Schneider et al., 2010; Williams et al., 2005). Hypointensive 237 signals from the basal ganglia on T2* weighted MRIs may have 238 indicated iron deposition in one KRS patient (Behrens et al., 2010; 239 Schneider et al., 2010); however, similar hypointensive signals were 240 not apparent in T2* weighted MRIs from three other KRS patients 241 (Crosiersetal.,2010;Santoroetal.,2010).Althoughatleast fi veofthe 242 KRS patients have died (Behrens et al., 2010; Williams et al., 2005), 243 brain histopathology was not reported. Analysis of a sural nerve 244 biopsy from one KRS patient revealed the presence of cytoplasmic 245 inclusions in Schwann cells and smooth muscle cells (Paisán-Ruiz et 246 al., 2010). 247 ATP13A2, the protein encoded by  ATP13A2 , is one of the four 248 members of the P5B subfamily of P-type ATPases (Sorensen et al., 249 2010).Thesetransmembraneproteinsbelongtoalargesuperfamilyof  250 P-type ATPases (Thever and Saier, 2009). Other P-type ATPases 251 regulate the transport of cations or phospholipids across biomem- 252 branes; however, the biologically relevant substrates have not been 253 determined for any of the P5 ATPases (Axelsen and Palmgren, 1998; 254 Bublitz et al., 2010). Ramirez et al. (2006) reported that epitope- 255 tagged and GFP-labeled ATP13A2 fusion products co-localized with 256 lysosomal markers when transiently transfected into COS7 cells, 257 suggesting that ATP13A2 regulates the distribution of its ligand 258 between cytoplasm and lysosome. Our observation that canine 259  ATP13A2  de fi ciency causes the lysosomal storage disease, NCL, is 260 consistent with this interpretation. MRIs indicative of iron deposition 261 in the basal ganglia of a KRS patient (Schneider et al., 2010; Behrens 262 et al., 2010) suggested that iron ions may be a substrate for ATP13A2. Fig. 3.  A Manhattan plot of -LOG 10 (P) values from a 19 case×15 control GWAS for the Tibetan terrier NCL locus calculated under a recessive model of inheritance.  Table 1 t1 : 1 Distribution of genotypes among normal and NCL-affected Tibetan terriers. t1 : 2t1 : 3  Disease Phenotype Genotype t1 : 4  del/del del/wt wt/wt del/wt+wt/wt Total t1 : 5  NCL con fi rmed a 33 0 0 0 33 t1 : 6  NCL ruled out b 0 0 3 3 3 t1 : 7  NCL suspected c 16 2 3 5 21 t1 : 8  No NCL-like signs at  N 10 years old 0 62 78 140 140 t1 : 9  No NCL-like signs at  b 10 years old 8 78 156 234 242 t1 : 10  Total 57 142 240 382 439 a Diagnosis of NCL con fi rmed by histopathology. t1 : 11 b Diagnosis of NCL ruled out by histopathology. t1 : 12 c Dog showed NCL-like behavioral changes but brain tissue unavailable for con fi rmation. t1 : 13 4  F.H.G. Farias et al. / Neurobiology of Disease xxx (2011) xxx –  xxx Please cite this article as: Farias, F.H.G., et al., A truncating mutation in  ATP13A2  is responsible for adult-onset neuronal ceroid lipofuscinosisin Tibetan terriers, Neurobiol. Dis. (2011), doi:10.1016/j.nbd.2011.02.009  263  Other experiments have demonstrated that the deletion of   ATP13A2 264  homolog  YPK9  in  Saccharomyces cerevisiae , rendered the yeast more 265  susceptible to the toxic effects of cadmium, manganese, nickel and 266  selenium ions (Schmidt et al., 2009), suggesting that one, or a 267  combination,oftheseionscouldbethebiologicallyrelevantsubstrate. 268  Even though homozygous truncating mutations in  ATP13A2  have 269  caused both KRS and adult-onset Tibetan terrier NCL, the resulting 270  disease phenotypes only partially overlap. Like the KRS patients, 271  NCL-affected Tibetan terriers exhibited cognitive decline, loss of  272  learnedbehaviors,disorientationandinappropriateaggression(Alroy 273  et al., 1992; Katz et al., 2001, 2002, 2005b, 2007; Riis et al. 1992). Also 274  similar to KRS patients, NCL-affected Tibetan terriers developed 275  diffuse brain atrophy as indicated by MRI in this study and a previous 276  report (Katz et al., 2005b). Nonetheless, the hypointensive signals in 277  T2* sequences from the basal ganglia, which suggested iron 278  deposition in a KRS patient (Behrens et al., 2010; Schneider et al., 279  2010), were absent from the Tibetan terrier images. The motor 280 abnormalities induced by  ATP13A2  de fi ciency also differed between 281 species. Unlike KRS patients, Tibetan terriers with NCL developed 282 cerebellar ataxia. On the other hand, the parkinsonism which was 283 predominant in the early stages of KRS was absent in the canine 284 disease.Themini-myoclonusreportedinKRShasnotbeenreportedin 285 the NCL-affected Tibetan terriers, although generalized tonic – clonic 286 seizures have occurred (Katz and O'Brien, unpublished observations). 287 Adult-onset Tibetan terrier NCL more closely resembles human 288 Kufs disease. Kufs disease families with both dominant and recessive 289 modes of inheritance have been described (Berkovic et al., 1988). 290 Berkovic et al. (1988) reviewed previous medical histories and 291 laboratory-test results from patients diagnosed with Kufs disease 292 and divided the cases into two categories: Type A in which the 293 predominant clinical feature was progressive myoclonic epilepsy and 294 Type B in which the predominant clinicalfeatures were dementia and 295 motor disturbances. More recent reports describe Kufs disease 296 families in which the patients cannot be categorized as Type A or Fig. 4. MRIsofaTibetan TerrierwithNCL(A&B)comparedto anage-matched, normal dog(C&D).OntheT1dorsalplanar images(A&C),theaffected dogshowsdilatedventriclesand widened sulci indicating diffuse brain atrophy (A). On T2* transverse views at the level of the basal ganglia (B & D), the ventricular dilation is also apparent in the affected dog(B), but there is no signal change in the caudate nuclei indicative of iron deposition.  Table 2 t2 : 1 Location and characteristics of sequence variants in  ATP13A2  from 28 Kufs disease patients. t2 : 2t2 : 3  Exonic location cDNA location Amino acid location In dbSNP? No. heterozygous:No. homozygous a Mutation type t2 : 4  Exon 6 c.G491A p.R164Q no 1:0 missense t2 : 5  Exon 11 c.C1005T p.A335A yes 2:0 synonymous t2 : 6  Exon 17 c.C1815T p.P605P yes 14:8 synonymous t2 : 7  Exon 24 c.C2637T p.G879G yes 9:7 synonymous t2 : 8  Exon 25 c.G2790A p.S930S yes 6:2 synonymous t2 : 9  Exon 26 c.G2970A p.V990V yes 10:7 synonymous t2 : 10  Exon 27 c.C3192T p.A1064A yes 10:7 synonymous t2 : 11  Exon 29 c.A3414G p.L1138L no 1:0 synonymous t2 : 12  Exon 29 c.G3516A p.P1172P yes 10:7 synonymous a Number of patients with variant allele in the heterozygous state: number of patients with variant allele in homozygous state. t2 : 13 5 F.H.G. Farias et al. / Neurobiology of Disease xxx (2011) xxx –  xxx Please cite this article as: Farias, F.H.G., et al., A truncating mutation in  ATP13A2  is responsible for adult-onset neuronal ceroid lipofuscinosisin Tibetan terriers, Neurobiol. Dis. (2011), doi:10.1016/j.nbd.2011.02.009
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