Neural and extraneural expression of the neuronal ceroid lipofuscinoses genes CLN1 , CLN2 , and CLN3 : functional implications for … (2000 Nov)
neural and extraneural expression of the neuronal ceroid lipofuscinoses genes CLN1 , CLN2 , and CLN3 : functional implications for CLN3 . The neuronal ceroid lipofuscinoses ( NCLs ) are the most common neurodegenerative disorders of childhood . We have examined mRNA levels of the CLN1 , CLN2 , and CLN3 genes , which are associated with the infantile , late infantile , and juvenile forms of NCL in 64 different human tissues , and have grouped the results into gastrointestinal tract , central nervous system , glandular / secretory , muscle , and carcinoma tissue types . mRNA levels for CLN3 are highest in gastrointestinal tissue and are also high in glandular / secretory tissue , whereas mRNA levels for CLN1 and CLN2 do not appear to be preferentially elevated in any tissue type . The significance of extraneural expression of CLN3 is reviewed in the context of the function of the protein .

The neuronal ceroid lipofuscinoses ( batten disease ) : a new class of lysosomal storage diseases. (1999 Sep)
The neuronal ceroid lipofuscinoses ( batten disease ) : a new class of lysosomal storage diseases . The neuronal ceroid lipofuscinoses ( batten disease ) are a group of severe neurodegenerative disorders characterized clinically by visual loss , seizures and psychomotor degeneration , and pathologically by loss of neurons and lysosomal accumulation of autofluorescent storage material resembling ageing pigment . To date , eight genetic loci have been identified ( CLN1 8 ) . Four CLN genes have been isolated ( CLN1 , CLN2 , CLN3 and CLN5 ) and their gene products have been characterized . CLN1 is a lysosomal palmitoyl protein thioesterase ( PPT ) and CLN2 is a lysosomal pepstatin insensitive peptidase . CLN3 and CLN5 are proteins with multiple membrane spanning regions and have no homologies to other proteins that would suggest their function . The CLN3 protein is associated with lysosomal membranes and the intracellular location of the CLN5 protein is unknown . therefore , there is ample evidence that the neuronal ceroid lipofuscinoses represent a new class of lysosomal storage disorders .

The neuronal ceroid lipofuscinoses. (1998 Mar)
The neuronal ceroid lipofuscinoses . recent advances . The neuronal ceroid lipofuscinoses ( NCLs ) represent a group of neurodegenerative disorders characterised by progressive visual failure , neurodegeneration , epilepsy and the accumulation of an autofluorescent lipopigment in neurons and other cells . The main childhood subtypes are infantile ( INCL ; CLN1 ) , classical late infantile ( lincl ; CLN2 ) and juvenile NCL ( JNCL ; CLN3 ) , distinguished on the basis of age of onset , clinical course and ultrastructural morphology , and recently genetic analysis . In addition several variant forms of the disease complex have been described as well as a rare adult onset form . advances in both genetics and biochemistry have led to the identification of the genes for the three main subtypes of childhood NCL and their corresponding protein products and to mapping of two additional genes for two variant forms . The disease causing genes in both INCL and classical lincl have been shown to encode lysosomal enzymes whilst the JNCL gene codes for a protein whose function is as yet unknown .

Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes 11p15 and 15q21 23. (1997 Jul)
Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes 11p15 and 15q21 23 . The childhood neuronal ceroid lipofuscinoses ( NCLs ) are a group of autosomal recessive neurodegenerative disorders characterised by progressive visual failure , neurodegeneration , epilepsy and the accumulation of an autofluorescent lipopigment in neurones and other cells . three main subtypes have been identified according to age of onset , clinical features and ultrastructural morphology . these are infantile NCL ( INCL ; CLN1 ) , classical late infantile NCL ( lincl ; CLN2 ) and juvenile NCL ( JNCL ; CLN3 ) . several atypical forms of late infantile NCL ( lincl ) have also been described including a finnish variant lincl ( CLN5 ) . The CLN2 gene has been excluded from the CLN1 , CLN3 and CLN5 loci . A genome search was initiated using a homozygosity mapping strategy in five classical lincl and two variant lincl consanguineous families . A common region of homozygosity was identified on chromosome 11p15 in two of the classical families . analysis of a further 33 classical lincl families supported linkage in this region ( Zmax 3 . 07 at theta 0 . 06 at d11s1338 ) . A common region of homozygosity was also observed on chromosome 15q21 23 in the two variant lincl families . extension of the analysis to include a further seven families of identical ultrastructural phenotype established linkage to this region ( Zmax 6 . 00 at …

Reevaluation of neuronal ceroid lipofuscinoses : atypical juvenile onset may be the result of CLN2 mutations. (1999 Jun)
reevaluation of neuronal ceroid lipofuscinoses : atypical juvenile onset may be the result of CLN2 mutations . This study describes the phenotype / genotype analyses of 56 probands with a juvenile onset , some of which had atypical features of neuronal ceroid lipofuscinosis , collected at the New York state institute for basic research ( IBR ) . In this group , we found probands with abundant curvilinear profiles in lysosomal storage material , deficiency of pepstatin insensitive peptidase , and mutations in the CLN2 gene , as well as patients with a predominance of granular osmiophilic deposits in the lysosomal storage material , deficiency of palmitoyl protein thioesterase , and mutations in the CLN1 gene . We have divided the probands into two categories : typical ( or classic ) and atypical . Most of the typical and atypical probands had onset of symptoms about or after 4 years of age . interfamiliar and intrafamiliar variations were found , especially in the speed of becoming practically blind . Thus , our study indicates that some mutations in the CLN1 , CLN2 , and CLN3 genes may be associated with late onset of the disease process , may have a more benign clinical course , and clinic overlap with other forms of neuronal ceroid lipofuscinosis .

Disease specific pathology in neurons cultured from sheep affected with ceroid lipofuscinosis. (1999 Jun)
disease specific pathology in neurons cultured from sheep affected with ceroid lipofuscinosis . The neuronal ceroid lipofuscinoses ( NCL , batten disease ) are a group of inherited neurodegenerative storage diseases in children . mutations in different genes underlie different forms . subunit c of mitochondrial ATP synthase is specifically stored in autofluorescent bodies in most of them , including a form in sheep . mature bodies are lysosomal but the initial site of storage is not known , nor is it known how this leads to the characteristic neurodegeneration . neurons were cultured in serum free medium from control and affected sheep fetuses at 90 days gestation . They showed positive microtubule associated protein staining , developed neurites , and had typical neuron morphology . Time dependent accumulation of subunit c and of fluorescent storage bodies was observed in affected cells by immunocytochemistry and confocal microscopy . A small number of autofluorescent bodies were apparent after 4 days in culture . after 10 days these bodies were more numerous , more intensely autofluorescent , and often larger in size . By 14 and 21 days many neurons were packed with autofluorescent material . these bodies were not seen in control cultures . immunocytochemistry revealed subunit c positive storage material only in affected neurons and not in affected glial cells . confocal microscope analysis , using organelle specific dyes , demonstrated colocalization of autofluorescent bodies with lysosomes , not with mitochondria . survival rates of the affected cells were unaffected …

A variant form of late infantile neuronal ceroid lipofuscinosis ( CLN5 ) is not an allelic form of batten ( … (1994 Aug)
A variant form of late infantile neuronal ceroid lipofuscinosis ( CLN5 ) is not an allelic form of batten ( spielmeyer Vogt sjögren , CLN3 ) disease : exclusion of linkage to the CLN3 region of chromosome 16 . The neuronal ceroid lipofuscinoses ( NCLs ) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types . The biochemical basis of these diseases is unknown . three main childhood forms are recognized : infantile ( santavuori haltia disease , CLN1 ) , late infantile ( jansky bielschowsky disease , CLN2 ) , and juvenile ( spielmeyer Vogt sjögren , batten disease , CLN3 ) . The CLN1 gene has been mapped to chromosome 1p and CLN3 to chromosome 16p by linkage analysis ( 1 , 2 ) . The gene locus causing the classical late infantile form ( CLN2 ) has not yet been mapped but has been excluded from both CLN1 and CLN3 loci ( 8 ) . about 10 of NCL cases have atypical clinical features with most of these resembling the late infantile form .

Targeted disruption of the Cln3 gene provides a mouse model for batten disease. (1999 Dec)
targeted disruption of the Cln3 gene provides a mouse model for batten disease . The batten mouse model consortium corrected batten disease , a degenerative neurological disorder with juvenile onset , is the most common form of the neuronal ceroid lipofuscinoses . mutations in the CLN3 gene cause batten disease . To facilitate studies of batten disease pathogenesis and treatment , a murine model was created by targeted disruption of the Cln3 gene . Mice homozygous for the disrupted Cln3 allele had a neuronal storage disorder resembling that seen in batten disease patients : there was widespread and progressive intracellular accumulation of autofluorescent material that by EM displayed a multilamellar rectilinear / fingerprint appearance . inclusions contained subunit c of mitochondrial ATP synthase . mutant animals also showed neuropathological abnormalities with loss of certain cortical interneurons and hypertrophy of many interneuron populations in the hippocampus . finally , as is true in batten disease patients , there was increased activity in the brain of the lysosomal protease Cln2 / TPP 1 . Our findings are evidence that the Cln3 deficient mouse provides a valuable model for studying batten disease .

Action of BTN1 , the yeast orthologue of the gene mutated in batten disease. (1999 May)
action of BTN1 , the yeast orthologue of the gene mutated in batten disease . neuronal ceroid lipofuscinoses ( NCL ) are autosomal recessive disorders that form the most common group of progressive neurodegenerative diseases in children , with an incidence as high as 1 in 12 , 500 live births , and with approximately 440 , 000 carriers in the united states . disease progression is characterized by a decline in mental abilities , increased severity of untreatable seizures , blindness , loss of motor skills and premature death . The CLN3 gene , which is responsible for batten disease , has been positionally cloned . The yeast gene , denoted BTN1 , encodes a non essential protein that is 39 identical and 59 similar to human CLN3 . strains lacking btn1p , btn1 delta , are resistant to D ( ) threo 2 amino 1 p nitrophenyl 1 , 3 propanediol ( ANP ) in a pH dependent manner . This phenotype was complemented by expression of human CLN3 , demonstrating that yeast btn1p and human CLN3 share the same function . Here , we report that btn1 delta yeast strains have an abnormally acidic vacuolar pH in the early phases of growth . furthermore , DNA microarray analysis of BTN1 and btn1 delta strains revealed differential expression of two genes , with at least one , hsp30 , involved in pH control . because btn1p is located in the vacuole , we suggest that batten disease is …

The neuronal ceroid lipofuscinoses ( batten disease ) : comparative aspects. (1995 Jul)
The neuronal ceroid lipofuscinoses ( batten disease ) : comparative aspects . The ceroid lipofuscinoses are a group of inherited neurodegenerative diseases of human beings characterized by the accumulation of a fluorescent lipopigment in neurons and other cells within the body . there is usually atrophy of both brain and retina with preferential loss of particular neurons . biochemically , the diseases divide into at least two groups , i . e . those that accumulate subunit c of mitochondrial ATP synthase and those that do not . dolichol pyrophosphate linked oligosaccharides are also present in storage material . As the underlying biochemical anomalies are not known , the various clinicopathological entities are classified on clinical grounds , by age of onset and , to a lesser extent , by the course of the disease . The best recognized diseases are infantile , late infantile , early juvenile , juvenile and adult onset forms but other variants occur indicating considerable heterogeneity within the group . The infantile , late infantile and juvenile diseases are not allelic . analogous diseases occur in a variety of animal species . That in the sheep has been extensively studied as a model of the human disease and is the prototype subunit c storage disease .

Stargardt s disease is not allelic to the genes for neuronal ceroid lipofuscinoses. (1994 Jul)
stargardt s disease is not allelic to the genes for neuronal ceroid lipofuscinoses . stargardt s disease is an autosomal recessive condition characterised by a rapid and bilateral loss of central vision at around 7 to 12 years , with typical changes in the macular and perimacular region . It is one of the most frequent causes of macular degeneration in childhood and accounts for 7 of all retinal dystrophies . considering that inclusions of lipofuscin like substances are observed in retinal pigmentary cells of patients with stargardt s disease on the one hand , and that the early symptoms of neuronal ceroid lipofuscinosis ( CLN3 ) are suggestive of stargardt s disease on the other hand ( age of loss of visual acuity , appearance of the fundus ) , we decided to test allelism of stargardt s disease with the infantile ( CLN1 ) and juvenile forms of neuronal ceroid lipofuscinosis ( CLN3 ) , which map to chromosomes 1p32 and 16p12 p11 respectively . using highly informative microsatellite DNA markers in eight multiplex families , we were able to exclude stargardt s disease from the vicinity of the CLN1 and CLN3 loci . these results strongly reject the hypothesis of allelism of stargardt s disease with the neuronal forms of ceroid lipofuscinosis .

Searching for interacting partners of CLN1 , CLN2 and btn1p with the two hybrid system. (2001 Oct)
searching for interacting partners of CLN1 , CLN2 and btn1p with the two hybrid system . The neuronal ceroid lipofuscinoses ( NCLs ) are the most common neurodegenerative disorders of childhood . The CLN1 , CLN2 and CLN3 genes are associated to the infantile , late infantile and juvenile forms of NCL , respectively . We have subcloned the cdnas encoding CLN1 , CLN2 and BTN1 , the yeast homologue of human CLN3 , into plasmid vectors to evaluate whether these proteins interact with other proteins co expressed from either a cDNA library derived from human cerebellum or from yeast , respectively , using the two hybrid system . We concluded that CLN1 most likely does not interact with any other proteins in vivo . furthermore , it is unlikely that CLN2 interacts with other proteins in vivo , although this study utilized a cDNA encoding the CLN2 precursor and it is possible that interacting partners may be excluded by the nature of this protein structure . finally , we conclude that proteins that interact with btn1p and therefore CLN3 cannot be identified using the whole proteins in a two hybrid system , due to the hydrophobic nature of this protein . By understanding the topology of CLN3 , specific regions of CLN3 need to be tested by two hybrid to identify any interacting partners .

Moving towards therapies for juvenile batten disease ? The neuronal ceroid lipofuscinoses ( NCLs or batten disease ) are a … (2008 May)
moving towards therapies for juvenile batten disease ? The neuronal ceroid lipofuscinoses ( NCLs or batten disease ) are a group of at least nine autosomal recessively inherited monogenetic storage disorders . because there are no effective therapies available , all forms of NCL invariably prove fatal after a prolonged period of disability . indeed , for the forms of NCL that are the result of mutations in transmembrane proteins , the therapeutic outlook remains uniformly bleak . This includes juvenile NCL ( JNCL ) ; the most prevalent form of batten disease that is the result of mutations in the CLN3 gene . characterizing Cln3 deficient mice is now revealing important clues about the pathogenesis of JNCL . This includes evidence for elevated levels of glutamate within the JNCL CNS and cell type selective sensitivity to alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionate ( AMPA ) type glutamate receptor overactivation . these findings raise the possibility that AMPA receptor blockade may potentially be beneficial in JNCL . This possibility has now begun to be tested in Cln3 mutant mice using a single intraperitoneal injection of the non competitive AMPA antagonist EGIS 8332 by kovács and pearce kovács , A . D . , pearce , D . A . , 2008 . attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile batten disease . Exp . neurol . 209 , 288 291 . . although a positive effect of upon motor coordination deficits …

Intracellular trafficking of CLN3 , the protein underlying the childhood neurodegenerative disease , batten disease. (2003 Dec)
intracellular trafficking of CLN3 , the protein underlying the childhood neurodegenerative disease , batten disease . juvenile neuronal ceroid lipofuscinoses ( batten disease ) is a progressive neurodegenerative disorder resulting from mutations in the CLN3 gene , which encodes a hydrophobic 438 amino acid protein of unknown function . prior studies have shown that CLN3 is expressed in multiple tissues , with highest levels in brain and testis . experiments using cells overexpressing CLN3 indicate that CLN3 is a lysosomal resident protein . however , studies to date have not addressed trafficking of endogenous CLN3 . As such , the purpose of the present study was two fold . first , to develop a culture model to allow evaluation of native CLN3 transport . second , to utilize available epitope specific antibodies to determine if CLN3 reaches the plasma membrane en route to the lysosome . Our data using a nccit ( embryonic testicular carcinoma ) cell model coupled with surface biotinylation and antibody trapping demonstrated that at least a proportion of CLN3 trafficks to the lysosome via the cell membrane . moreover , inhibition of the micro3a subunit of the AP 3 adapter protein complex increased levels of CLN3 at the cell surface .

High resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not … (2004 Sep)
High resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not in CLN3 . The neuronal ceroid lipofuscinoses ( NCLs ) are among the most severe inherited progressive neurodegenerative disorders of children . The purpose of this study was to compare the in vivo 1 . 5 T 1H magnetic resonance ( MR ) and ex vivo 14 . 3 T high resolution ( HR ) magic angle spinning ( MAS ) 1H MR brain spectra of patients with infantile ( CLN1 ) and juvenile ( CLN3 ) types of NCL , to obtain detailed information about the alterations in the neuronal metabolite profiles in these diseases and to test the suitability of the ex vivo HR MAS ( 1 ) H MRS technique in analysis of autopsy brain tissue . Ex vivo spectra from CLN1 autopsy brain tissue ( n 9 ) significantly differed from those of the control ( n 9 ) and CLN3 ( n 5 ) groups , although no differences were found between the CLN3 and the control groups . principal component analysis of ex vivo data showed that decreased levels of N acetylaspartate ( NAA ) , gamma aminobutyric acid ( GABA ) , glutamine , and glutamate as well as increased levels of inositols characterized the CLN1 spectra . Also , the intensity ratio of lipid methylene / methyl protons was decreased in spectra of CLN1 brain tissue compared with CLN3 and control brain …

Incidence of neuronal perikaryal spheroids in neuronal ceroid lipofuscinoses ( batten disease ). (1998 Nov)
incidence of neuronal perikaryal spheroids in neuronal ceroid lipofuscinoses ( batten disease ) . The stored material in neuronal ceroid lipofuscinosis ( NCL ) undergoes , irrespective of the disease type , a uniform modification , altering profoundly its physical and histochemical properties . The process is accompanied by loss of immunodetectable epitopes of subunit c of mitochondrial ATP synthase ( scmas ) in the transformed storage material in NCL2 and NCL6 and of sphingolipid activator proteins ( SAPs ) A and D in NCL1 , NCL2 , and NCL6 . It is restricted to certain subcortical brain nuclei , typically nucleus niger , dentatus , lentiformis , and thalamus . The process is coupled with progressive enlargement of the deposits caused probably by aggregation and fusion of the storage lysosomes . This ensues in formation of larger pleiomorphic perikaryal corpuscles , the spheroids being only one special form in the spectrum . The process was found to be most intensive in NCL2 brains . As the neuronal unmodified storage deposits tend also to be present in aggregate form , care must be taken to distinguish spheroids composed of modified from those composed of unmodified storage material .

CNS directed AAV2 mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. (2006 Feb)
CNS directed AAV2 mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis . The neuronal ceroid lipofuscinoses ( batten disease ) are a group of inherited neurodegenerative diseases characterized by the progressive intralysosomal accumulation of autofluorescent material in many cells , visual defects , seizures , cognitive deficits , and premature death . infantile neuronal ceroid lipofuscinosis ( INCL ) has the earliest onset ( approximately 1 . 5 years of age ) and is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase 1 ( PPT1 ) . currently there is no effective treatment for children with INCL . In this study , newborn PPT1 deficient mice received two ( cortex ) , four ( cortex and hippocampus ) , or six ( cortex , hippocampus , and cerebellum ) bilateral intracranial injections of AAV2 PPT1 . The AAV treated animals had localized increases in PPT1 activity , decreased autofluorescent material , improved histologic parameters , and increased brain mass . In addition , the treated animals had dose dependent improvements in a battery of behavioral tests and improved interictal electroencephalographic tracings . however , there was neither a significant decrease in seizure frequency nor an increase in longevity even in INCL animals receiving six injections . these data suggest that early treatment of INCL using gene transfer techniques can be efficacious . however , higher levels or a broader distribution of PPT1 expression , or both , will be required …

From gene to disease ; from CLN1 , CLN2 and CLN3 to neuronal ceroid lipofuscinosis The neuronal ceroid lipofuscinoses ( … (2005 Feb)
From gene to disease ; from CLN1 , CLN2 and CLN3 to neuronal ceroid lipofuscinosis The neuronal ceroid lipofuscinoses ( NCL ) are worldwide the most common lysosomal storage disorders of childhood . clinical features often include progressive visual impairment , seizures , psychomotor deterioration , dementia , and premature death . Most NCL cases are caused by mutations in the CLN1 , CLN2 and CLN3 genes , which play an essential role in lysosomal protein degradation . laboratory diagnostics for a patient suspected of NCL should start with enzyme analysis in the case of INCL and lincl and investigation of lymphocyte vacuolisation for JNCL . diagnosis at the protein level is not available for JNCL , but CLN3 mutation analysis is possible . The carrier status of healthy relatives in families with known mutations in either CLN1 , CLN2 , CLN3 or CLN6 can be determined with certainty by mutation analysis .

Molecular genetics of the neuronal ceroid lipofuscinoses. (1999 Aug)
molecular genetics of the neuronal ceroid lipofuscinoses . The neuronal ceroid lipofuscinoses ( NCLs ) are a group of inherited neurodegenerative disorders characterised by the accumulation of autofluorescent storage material in neurons and other cell types . The clinical features include visual impairment , progressive myoclonic epilepsy , and cognitive decline reflecting progressive neurodegeneration . The NCLs are subdivided into several subtypes according to age of onset , clinical course , and ultrastructure of the storage material . The molecular genetic basis of this group of disorders has recently been clarified . mutations in the gene encoding a lysosomal enzyme , palmitoyl protein thioesterase ( PPT ) , cause infantile NCL ( locus CLN1 on chromosome 1p32 ) or haltia santavuori disease . This finnish disease is characterised ultrastructurally by granular osmiophilic deposits ( grods ) . juvenile onset NCL with grods also is caused by mutations in PPT . classic late infantile NCL ( jansky bielschowsky disease ) is caused by mutations in a gene encoding a pepstatin insensitive lysosomal peptidase ( CLN2 on chromosome 11p15 ) , and juvenile onset NCL ( batten disease ) is caused by mutations in a gene encoding a 438 amino acid membrane protein ( CLN3 on chromosome 16p12 ) of unknown function . A locus for finnish variant late infantile NCL , CLN5 , has been mapped to chromosome 13q22 and a locus for variant late infantile NCL , CLN6 , to chromosome 15q21 23 . these and further advances will allow …

Lectin histochemistry in brains with juvenile form of neuronal ceroid lipofuscinosis ( batten disease ). (1990 Oct)
lectin histochemistry in brains with juvenile form of neuronal ceroid lipofuscinosis ( batten disease ) . defective utilization of dolichols in the synthesis of glycoprotein leads to an accumulation of the storage , pigment ceroid lipofuscin , containing high mannose type glycoconjugates , in brains affected by neuronal ceroid lipofuscinoses ( NCL ) . We have employed lectin histochemistry to study the distribution of such compounds and the composition of other glycoconjugates in brains of patients with a juvenile form of the disease ( JNCL ) . concanavalin A detected the high mannose glycoconjugates in all neurons of brains with JNCL , in lipofuscin containing neurons of aging brains and in some neurons of age matched control brains . three other lectins ( soybean agglutinin , peanut agglutinin and Ulex europaeus agglutinin I ) recognized sugar moieties in neurons containing lipofuscin in patients only with JNCL and not in age matched or aging brains . The results led to the conclusion , that the binding pattern of these three lectins may differentiate between storage materials of NCL and aging brains .