Disease relevance of CLN6

• CLN6, which is associated with a lysosomal storage disease, is an endoplasmic reticulum protein [1].
• The CLN6 gene that causes variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a recessively inherited neurodegenerative disease that features blindness, seizures, and cognitive decline, maps to 15q21-23 [2].

High impact information on CLN6

• Thus, the novel approximately 36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes NCL in mouse and man [2].
• We have used multiallele markers spanning this approximately 4-Mb candidate interval to reveal a core haplotype, shared in Costa Rican families with vLINCL but not in a Venezuelan kindred, that highlighted a region likely to contain the CLN6 defect [2].
• Extensive neuronal death is seen in CLN2- and CLN3-deficient human brain as well as in CLN6-deficient sheep brain and retina [3].
• Using double immunofluorescence microscopy, epitope-tagged CLN6 was shown to be retained in the endoplasmic reticulum (ER) with no colocalization with the cis-Golgi or lysosomal markers [4].
• The translocation into the ER and proper folding were confirmed by the N-linked glycosylation of a mutant CLN6 polypeptide [4].

Biological context of CLN6

• 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 [5].
• A missense mutation (c.184C>T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA [6].
• The gene for variant late-infantile NCL (vLINCL), CLN6, was previously mapped to chromosome 15q21-23 and is predicted to be orthologous to the genes underlying NCL in nclf mice and in South Hampshire and Merino sheep [7].
• In this study, transient transfection of BHK21 cells with CLN6 cDNA and immunoblot analysis using peptide-specific CLN6 antibodies demonstrated the expression of a approximately 27-kDa protein that does not undergo proteolytic processing [4].
• No mutations were found in the coding exons and splicing junctions of NR2E3, SMAD6, and CLN6 [8].

Anatomical context of CLN6

• Using immunofluorescence microscopy, CLN6 was shown to reside in the endoplasmic reticulum (ER) [1].
• These data support suggestions that neurodegeneration and storage body accumulation may be independent manifestations of CLN6 mutation and indicate that glial cell activation may be an important mediator in pathogenesis [9].
• Gene expression profiling in vLINCL CLN6-deficient fibroblasts: Insights into pathobiology [10].
• Cell type specific neurodegeneration in these sheep was indicated by the distribution of GABAergic interneurons in coronal sections of normal and CLN6 affected sheep brains [11].
• Confocal fluorescence microscopy and immunohistochemical studies revealed the presence of MnSOD in mitochondria of CLN6 fibroblasts and in CLN6 brain sections within both neurons and hypertrophic astrocytes [12].

Associations of CLN6 with chemical compounds

• In two families, we identified two novel homozygous mutations in the CLN6 gene: an intronic base substitution (c.542+5G>T) affecting the splicing of the transcript and a nonsense mutation (c.663C>G) creating a stop codon at tyrosine 221 [13].
• Up-regulated genes related to steroidogenesis or signalling, and the relationship between cholesterol dynamics and glycosphingolipid sorting, led to investigation of free cholesterol and gangliosides in CLN6-deficient fibroblasts [10].

Other interactions of CLN6

• Two other genes, CLN6 and CLN7, have been assigned recently to small chromosomal regions [14].
• These data indicate that CLN6 mutations, in addition to those of CLN8, should be considered a diagnostic alternative in Turkish vLINCL patients [13].
• Subunit c of mitochondrial ATP synthase specifically accumulates in most of them, including the juvenile CLN3 form and a sheep form orthologous to CLN6 [15].
• Three candidate genes, NR2E3, SMAD6, and CLN6, located within the critical region, were screened for mutations [8].

Analytical, diagnostic and therapeutic context of CLN6

• Antisera raised against CLN6 peptides detected a protein of 30 kDa by Western blotting of human cells, which was missing in cells from some CLN6 deficient patients [1].
• 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 [6].
• Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6 [16].
• In the present study gene expression profiling of CLN6-deficient fibroblasts using cDNA microarray was undertaken in order to provide novel insights into the molecular mechanisms underlying this neurodegenerative fatal disease [10].
• YAC clones that span the critical region have been isolated and comparative gene mapping confirms that the regions for CLN6 and OCL are equivalent [17].

References