Disease relevance of CLN5

• Both CLN3 and CLN5 mouse models will provide experimental tools to resolve the pathological cascade in these neurodegenerative diseases [1].
• NCL are considered as lysosomal storage diseases because of the accumulation of autofluorescent inclusion bodies [2].
• A missense mutation in CLN8 causes progressive epilepsy with mental retardation (EPMR) or Northern epilepsy, which has so far been reported only from Finland and is now classified as an NCL [3].
• The variant form of late infantile neuronal ceroid lipofuscinosis (vLINCL, locus definition CLN5) represents a progressive brain disease with autosomal recessive inheritance [4].
• Clinical signs of a new canine NCL began in a 9-month-old male Dachshund with vomiting, mental dullness, and loss of previously learned commands and rapidly progressed to include disorientation, ataxia, visual deficits, generalized myoclonic seizures, and death at 12 months of age [5].

Psychiatry related information on CLN5

• Sleep disorders are common in NCL patients [6].
• The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain [7].
• Clinical symptomatology differs from the classical childhood NCL forms in that ocular symptoms are absent while changes of behavior, dementia and seizures dominate the clinical picture [8].

High impact information on CLN5

• Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype (CLN8) [9].
• Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL [9].
• All types of NCL cause progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes, and lead to premature death [10].
• The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years, and characteristic storage bodies are found in brain and other tissues at autopsy [11].
• These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease [12].

Chemical compound and disease context of CLN5

• Deficiency in a recently characterized lysosomal enzyme, palmitoyl-protein thioesterase (PPT), leads to a severe neurodegenerative disorder of children, infantile neuronal ceroid lipofuscinosis (NCL) [13].
• We have measured the LPIP activities in brains from various forms of human neuronal ceroid lipofuscinoses (NCL), canine ceroid lipofuscinosis and other neurodegenerative disorders with a highly sensitive assay using a tetrapeptide Gly-Phe-Phe-Leu-amino-trifluoromethyl coumarin (AFC) as substrate [14].
• In the current study, using subtraction cloning for genes that are differentially expressed in metastasis, the authors isolated a clone encoding ceroid lipofuscinosis, neuronal 2 (CLN2), which is a lysosomal serine protease defective in neuronal ceroid lipofuscinosis (NCL) [15].
• Therefore, the normal laboratory diets of NCL dogs were supplemented with carnitine, fish oil and corn oil and the disease progression was compared with that of an untreated litter mate [16].
• Adult Neuronal Ceroid Lipofuscinosis (Adult NCL), also known as Kuf's Disease, is a rare progressive encephalopathic disease that results in dementia [17].

Biological context of CLN5

• Both intracellular targeting and posttranslational glycosylation of the polypeptides carrying human disease mutations were similar to wild-type CLN5 [18].
• 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 [19].
• Using the 3 microsatellite markers which were most tightly linked to CLN5, we have excluded CLN2 from this region using a subset of 17 families [20].
• Recent promising molecular genetic studies have, however, revealed the gene for infantile neuronal ceroid-lipofuscinosis, CLN1, on chromosome 1p32; the gene for juvenile neuronal ceroid-lipofuscinosis, CLN3, on chromosome 16p12.1-11.2; and the gene for a Finnish variant of late-infantile neuronal ceroid-lipofuscinosis, CLN5, on chromosome 13q31-32 [21].
• DNA analysis showed that the fetus had inherited the major mutation, a 2 bp deletion of the CLN5 gene from the mother, and the same paternal (and maternal) haplotypes for COLAC1 and AC224 as the affected daughter [22].

Anatomical context of CLN5

• The CLN3 protein is associated with lysosomal membranes and the intracellular location of the CLN5 protein is unknown [23].
• The CLN3 and CLN5 genes show ubiquitous expression patterns and are targeted to lysosomes in vitro, but the observed synaptosomal localization of the CLN3 protein in neurons would suggest some cell specificity in targeting and function of these proteins [1].
• As cattle are anatomically and physiologically similar to humans with a human-like central nervous system and easy to maintain and breed, they provide a valuable alternative model for CLN5 studies [24].
• The composition of inclusion bodies varies in different forms of the NCL [2].
• Electron microscopy of a chorionic villus sample (CVS) at the 11th week of gestation did not reveal inclusions characteristic for NCL [22].

Associations of CLN5 with chemical compounds

• Mutations in the gene encoding a lysosomal enzyme, palmitoyl protein thioesterase (PPT), cause infantile NCL (locus CLN1 on chromosome 1p32) or Haltia-Santavuori disease [25].
• Linkage analysis established that CLN6 is the gene most likely to cause NCL in affected South Hampshire sheep, which do not have the c.184C>T mutation but show reduced expression of CLN6 mRNA in a range of tissues as determined by real-time PCR [26].
• The same-sized glycosylated polypeptides were also observed in the media, suggesting that the 60 kDa glycosylated CLN5 polypeptide represents a soluble lysosomal glycoprotein, not an integral transmembrane protein as predicted earlier [27].
• Furthermore, HR MAS 1H MR spectra facilitated refined detection of neuronal metabolites, including GABA, and composition of lipids in the autopsy brain tissue of NCL patients [28].
• Carnitine and polyunsaturated fatty acids have been reported to be reduced in NCL English Setters [16].

Other interactions of CLN5

• The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited severe neurodegenerative disorders primarily affecting children [29].
• Genomic and proteomic approaches have presently identified eight different forms of NCL (namely, CLN1 through CLN8) based on mutations in specific genes [2].
• Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL) [30].
• These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl) [30].
• Genetic variants such as CLN6 might therefore cause a significant portion of childhood NCL in the Portuguese population.The relative frequency of classical childhood forms of NCL in the Portuguese population is reported and contributes to the knowledge of genetic epidemiology of these world-widely distributed disorders [31].

Analytical, diagnostic and therapeutic context of CLN5

• Prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis (vLINCL[Finnish]; CLN5) [22].
• This mutation causes a frame-shift and premature termination (p.Arg221GlyfsX6) which is predicted to result in a severely truncated protein, analogous to disease causing mutations in human Finnish late infantile variant NCL (CLN5), and a simple genetic diagnostic test has been developed [24].
• Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice [32].
• Although the clinical phenotype of these NCL subtypes differs in the age of onset, average life span and EEG findings, the major component of material accumulating in patients' lysosomes is subunit c of mitochondrial ATPase in both these diseases [1].
• Confocal immunofluorescence microscopy showed that wild-type CLN5 is predominantly targeted to lysosomes and immunoprecipitation analysis recognized a 60 kDa polypeptide [27].

References