Alternative titles; symbols
HGNC Approved Gene Symbol: CLN6
Cytogenetic location: 15q23 Genomic coordinates (GRCh38) : 15:68,206,992-68,257,211 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q23 | Ceroid lipofuscinosis, neuronal, 6A | 601780 | Autosomal recessive | 3 |
| Ceroid lipofuscinosis, neuronal, 6B (Kufs type) | 204300 | Autosomal recessive | 3 |
By positional cloning in the candidate region for variant late infantile neuronal ceroid lipofuscinosis (vLINCL, CLN6A; 601780) on chromosome 15q21-q23, Gao et al. (2002) identified the CLN6 (FLJ0561) gene. CLN6 encodes a deduced 311-amino acid protein with 7 predicted transmembrane domains and a predicted molecular mass of 36 kD. Northern blot analysis detected expression of a major 2.4-kb CLN6 mRNA in adult and embryonic brain and in peripheral tissues of mouse and human. The protein is conserved across vertebrates.
Gao et al. (2002) determined that the CLN6 gene contains 7 exons that span approximately 23 kb of genomic DNA.
By sequence analysis, Gao et al. (2002) identified the CLN6 gene on chromosome 15q21-q23. Bronson et al. (1998) demonstrated that the mouse Cln6 gene is on chromosome 9 in a region showing syntenic homology with human 15q21-q23.
By analyzing the isolated lysosome-enriched fractions from the livers of Cln6 -/- mice, Bajaj et al. (2020) showed that Cln6 deficiency resulted in the depletion of various lysosomal enzymes from the lysosomal compartment, and that the cause of the lysosomal enzyme depletion was posttranslational. Bimolecular fluorescence complementation (BiFC) assays revealed that Cln6 interacted with Cln8 (607837) in the ER and did not traffic to the Golgi complex. Cln8 is localized to the ER and the ER-Golgi intermediate compartment; Cln8 trafficking to the Golgi was found to be uncoupled from its interaction with Cln6. Immunoprecipitation analysis showed that Cln6 also interacted with lysosomal enzymes. The interaction required the second luminal loop of Cln6, and Cln6 and Cln8 were mutually necessary for their interaction with lysosomal enzymes. Cln6 and Cln8 functioned as obligate partners in the recruitment of newly synthesized lysosomal enzymes in the ER, but the subsequent transfer of enzymes to the Golgi was mediated by Cln8 only. Analysis with Cln6 and Cln8 single- or double-knockout mice indicated that Cln6 and Cln8 worked as a functional unit in vivo, as loss of Cln6 did not aggravate pathology of Cln8-deficient mice and vice vera.
Neuronal Ceroid Lipofuscinosis 6A
By sequence analysis, Gao et al. (2002) identified homozygosity for mutations in the CLN6 gene in affected members of 2 families with variant late infantile CLN (CLN6A; 601780): a G-to-T transversion in exon 3 in a Costa Rican family (606725.0001) and a codon deletion in exon 5 in a Venezuelan family (606725.0002).
Wheeler et al. (2002) independently and simultaneously identified 6 different mutations in the CLN6 gene in patients with a variant form of late infantile CLN (CLN6A).
Sharp et al. (2003) identified 8 mutations in the CLN6 gene in patients with CLN6A, bringing to 18 the total number of CLN6 mutations found in this disorder. Ten mutations affected single amino acids, all of which are conserved across the vertebrate species. Minor differences in the pattern of disease symptom evolution could be identified. One patient with a more protected disease course was a compound heterozygote for a missense mutation and an unidentified mutation. Fifteen mutations occurred in 1 or 2 families only, and families from the same country did not all share the same mutation. No major founder mutation was identified, but the glu72-to-ter mutation (606725.0001) was significantly more common in patients in Costa Rica than 2 other mutations present in that same population. A group of Roma Gypsy families from the Czech Republic shared 2 disease associated haplotypes, 1 of which is also present in a Pakistani family, consistent with the proposed migration of the Roma from the Indian subcontinent 1,000 years ago.
In 2 sibs and an unrelated patient with CLN6A without visual impairment, Chin et al. (2019) identified homozygous and compound heterozygous mutations in the CLN6 gene (606725.0015-606725.0017), respectively. The mutations were found by whole-exome sequencing.
Neuronal Ceroid Lipofuscinosis 6B (Kufs Type)
By genomewide mapping followed by candidate gene sequencing in 3 families with autosomal recessive neuronal ceroid lipofuscinosis (CLN6B; 204300), Arsov et al. (2011) identified homozygous or compound heterozygous mutations in the CLN6 gene (see, e.g., 606725.0011-606725.0014). Mutations were also found in affected members from 4 additional families with Kufs disease, yielding a total of 9 different pathogenic mutations in the CLN6 gene. All patients in the 7 families presented with progressive myoclonic epilepsy followed by dementia, consistent with a type A Kufs phenotype. There were no apparent genotype/phenotype correlations. Mutation in the CLN6 gene was not found in 1 family with a type B Kufs phenotype. Arsov et al. (2011) noted the striking phenotypic differences between patients with earlier onset CLN and patients with Kufs disease. Patients with CLN6A have retinal involvement, whereas none of the Kufs disease patients had retinal involvement. The authors suggested that Kufs disease patients may have some residual mutant protein function or that there are other disease modifiers.
In 13 unrelated families with CLN6B, Berkovic et al. (2019) identified homozygous CLN6 variants in 4 families and compound heterozygous variants in 9. Most pathogenic variants were predicted to result in amino acid substitutions; however, there were 4 heterozygous pathogenic variants predicting protein truncations, including 2 small deletions and/or insertions (indels), 1 large deletion, and 1 canonical splice site change. Compared to variants reported in the variant late infantile form (see 601780), fewer variants predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both the variant late infantile form and adult-onset Kufs disease; whether onset was in late infancy or adulthood depended on the mutation severity of the second allele. Of the 13 families, 9 were of Italian ancestry. The authors noted that this was likely a product of these rare pathogenic variants being founder mutations in mainland Italy, Sicily, and Malta.
Both Gao et al. (2002) and Wheeler et al. (2002) identified mutations in the Cln6 gene in the nclf mouse, which manifests a recessive NCL-like disease.
Kielar et al. (2009) reported a progressive breakdown of axons and synapses in the brains of 2 different mouse models of NCL: the Ppt1 (600722)-null mouse model of infantile NCL (CLN1; 256730) and the nclf mouse model of late infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the 2 NCL mouse models studied, 2 of the 15 proteins examined Vdac1 (604492) and Pttg1 (604147) displayed robust and significant changes at pre/early-symptomatic time-points in both strains of NCL mice. Kielar et al. (2009) concluded that synapses and axons are important early pathologic targets in the NCLs.
In a Costa Rican family with variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780), Gao et al. (2002) identified a G-to-T transversion at nucleotide 317 in exon 3 of the CLN6 gene, introducing a stop codon (E72X). The mutation was present in homozygous state. The same mutation was demonstrated in 6 Costa Rican kindreds by Wheeler et al. (2002).
In affected members of a Venezuelan family with variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780), Gao et al. (2002) identified homozygosity for a deletion of codon 171 (CTA) in exon 5 of the CLN6 gene, producing loss of tyr171 from the protein product.
In a Costa Rican family, Wheeler et al. (2002) found that variant neuronal ceroid lipofuscinosis (CLN6A; 601780) was associated with a 368G-A transition in the CLN6 gene, resulting in a gly123-to-asp (G123D) substitution.
In a family from Greece, Wheeler et al. (2002) found that variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780) was due to homozygosity for a 1-bp deletion, 6delG, in the CLN6 gene. This caused a frameshift after glu2 with 29 extra amino acids.
In 2 Pakistani families with variant late infantile neuronal ceroid lipofuscinosis (CLN6; 601780), Wheeler et al. (2002) found homozygosity for a 1-bp insertion, 316insC, producing a frameshift after pro105 with 25 extra amino acids.
In an Indian family with variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780), Wheeler et al. (2002) found a 2-bp deletion, 395_396delCT, in the CLN6 gene. This caused a frameshift after asp131 with 17 extra amino acids.
In a family from Portugal, Wheeler et al. (2002) found that variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780) was caused by a 3-bp deletion (460_462delATC) in exon 4 of the CLN6 gene, resulting in the loss of the ile154 codon (I154del).
Teixeira et al. (2003) concluded that the I154del mutation accounts for 81.25% of mutated CLN6 alleles in Portuguese patients with CLN6A.
In 2 Turkish sibs with variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780), Siintola et al. (2005) identified a homozygous 663C-G transversion in exon 6 of the CLN6 gene, resulting in a tyr221-to-ter (Y221X) substitution. The mutation was not identified in 119 Turkish control chromosomes.
In a Turkish patient with variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780), Siintola et al. (2005) identified a homozygous G-to-T transversion in intron 5 of the CLN6 gene, resulting in frameshifts with premature termination of the protein and absence of a functional CLN6 protein. The mutation was not identified in 119 Turkish control chromosomes.
In a patient of Irish, French, and Native American origin with neuronal ceroid lipofuscinosis (CLN6A; 601780), Teixeira et al. (2003) identified a 4-bp duplication in exon 3 of the CLN6 gene (267_268insAACG), resulting in truncation of the protein.
In affected members of 5 families with CLN6A, Moore et al. (2008) identified a homozygous 4-bp duplication, which they called 268_271dup, resulting in a frameshift and premature termination (Val91GlufsTer42). All the families were from the southern coast of Newfoundland, suggesting a founder effect.
In 2 Italian sibs with adult-onset neuronal ceroid lipofuscinosis-6B (CLN6B; 204300), Arsov et al. (2011) identified compound heterozygosity for 2 mutations in the CLN6 gene: a 200T-C transition in exon 3, resulting in a leu67-to-pro (L67P) substitution, and a 308G-A transition in exon 4, resulting in an arg103-to-gln (R103Q; 606725.0012) substitution. Both mutations occurred in highly conserved residues and were not found in 360 control chromosomes. The patients had onset at ages 16 and 36 years, respectively. Features included action myoclonus, tonic-clonic seizures, and later onset of dementia; ataxia was not present.
For discussion of the arg103-to-gln (R103Q) mutation in the CLN6 gene that was found in compound heterozygous state in patients with adult-onset neuronal ceroid lipofuscinosis-6B (CLN6B; 204300) by Arsov et al. (2011), see 606725.0011.
In an Italian woman, born of consanguineous parents, with neuronal ceroid lipofuscinosis-6B (CLN6B; 204300), Arsov et al. (2011) identified a homozygous 139C-T transition in exon 2 of the CLN6 gene, resulting in a leu47-to-phe (L47F) substitution at a highly conserved residue. The mutation was not found in 360 control chromosomes. The patient had onset of tonic-clonic seizures and massive myoclonus at age 28, followed by ataxia and dementia.
In a Canadian woman with neuronal ceroid lipofuscinosis-6B (CLN6B; 204300), previously reported by Berkovic et al. (1988), Arsov et al. (2011) identified a homozygous 17G-C transversion in exon 1 of the CLN6 gene, resulting in an arg6-to-thr (R6T) substitution at a highly conserved residue. The mutation was not found in 360 control chromosomes. The patient had onset of tonic-clonic seizures at age 31, followed by myoclonus and dementia; ataxia was not present. Berkovic et al. (1988) reported that the parents and 3 younger sibs were unaffected. The patient had a deceased affected sister and a maternal aunt with seizures from the age of 17 years. Ancestors of both parents were from adjacent small towns in the Italian province of Frosinone.
In a 15-year-old girl (proband 1) with variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780), Chin et al. (2019) identified compound heterozygous mutations in the CLN6 gene: a 3-bp duplication (c.218_220dupGGT), resulting in a duplication of tryptophan-73, and a c.296A-G transition, resulting in a lys99-to-arg (K99R; 606725.0016) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. Analysis in patient fibroblasts showed that CLN6 mRNA expression was unaltered, and CLN6 protein expression was slightly increased. The patient had developmental regression, ataxia, and progressive myoclonic epilepsy, but no visual impairment.
For discussion of the c.296A-G transition in the CLN6 gene, resulting in a lys99-to-arg (K99R) substitution, that was found in compound heterozygous state in a patient with variant late infantile neuronal ceroid lipofuscinosis (CLN6A; 601780) by Chin et al. (2019), see 606725.0015.
In a sister (proband 2) and brother with variant late infantile neuronal ceroid lipofuscinosis-6A (CLN6A; 601780), Chin et al. (2019) identified homozygosity for a c.723G-T transversion in the CLN6 gene, resulting in a met241-to-ile (M241I) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Analysis in fibroblasts from one of the sibs showed that mRNA expression was unaltered. CLN6 protein expression in the fibroblasts was slightly increased, with a significant increase in the monomeric form of CLN6, suggesting that the mutation may affect protein dimerization. The sibs had clinical features including developmental regression and ataxia, but no visual impairment.
In a 29-year-old woman with neuronal ceroid lipofuscinosis-6B (Kufs type) (CLN6B; 204300), Cherian et al. (2021) identified a homozygous c.350T-G transversion in exon 4 of the CLN6 gene, resulting in an ile117-to-ser (I117S) substitution. The mutation was found by next-generation sequencing. Functional studies of the variant were not performed.
Arsov, T., Smith, K. R., Damiano, J., Franceschetti, S., Canafoglia, L., Bromhead, C. J., Andermann, E., Vears, D. F., Cossette, P., Rajagopalan, S., McDougall, A., Sofia, V., and 10 others. Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. Am. J. Hum. Genet. 88: 566-573, 2011. [PubMed: 21549341] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.004]
Bajaj, L., Sharma, J., di Ronza, A., Zhang, P., Eblimit, A., Pal, R., Roman, D., Collette, J. R., Booth, C., Chang, K. T., Sifers, R. N., Jung, S. Y., Weimer, J. M., Chen, R., Schekman, R. W., Sardiello, M. A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer. J. Clin. Invest. 130: 4118-4132, 2020. [PubMed: 32597833] [Full Text: https://doi.org/10.1172/JCI130955]
Berkovic, S. F., Carpenter, S., Andermann, F., Andermann, E., Wolfe, L. S. Kufs' disease: a critical reappraisal. Brain 111: 27-62, 1988. [PubMed: 3284607] [Full Text: https://doi.org/10.1093/brain/111.1.27]
Berkovic, S. F., Oliver, K. L., Canafoglia, L. Krieger, P., Damiano, J. A., Hildebrand, M. S., Morbin, M., Vears, D. F., Sofia, V., Giuliano, L., Garavaglia, B., Simonati, A., and 19 others. Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features. Brain 142: 59-69, 2019. [PubMed: 30561534] [Full Text: https://doi.org/10.1093/brain/awy297]
Bronson, R. T., Donahue, L. R., Johnson, K. R., Tanner, A., Lane, P. W., Faust, J. R. Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9. Am. J. Med. Genet. 77: 289-297, 1998. [PubMed: 9600738] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980526)77:4<289::aid-ajmg8>3.0.co;2-i]
Cherian, A., K. P. D., Paramasivan, N. K., Krishnan, S. Pearls & oy-sters: levodopa-responsive adult NCL (type B Kufs) disease due to CLN6 mutation. Neurology 96: e2662-e2665, 2021. [PubMed: 33875558] [Full Text: https://doi.org/10.1212/WNL.0000000000011997]
Chin, J. J., Behnam, B., Davids, M., Sharma, P., Zein, W. M., Wang, C., Chepa-Lotrea, X., Gallantine, W. B., Toro, C., Adams, D. R. Tifft, C. J., Gahl, W. A., Malicdan, M. C. V. Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients. Molec. Genet. Metab. 126: 188-195, 2019. [PubMed: 30528883] [Full Text: https://doi.org/10.1016/j.ymgme.2018.12.001]
Gao, H., Boustany, R.-M. N., Espinola, J. A., Cotman, S. L., Srinidhi, L., Antonellis, K. A., Gillis, T., Qin, X., Liu, S., Donahue, L. R., Bronson, R. T., Faust, J. R., Stout, D., Haines, J. L., Lerner, T. J., MacDonald, M. E. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am. J. Hum. Genet. 70: 324-335, 2002. [PubMed: 11791207] [Full Text: https://doi.org/10.1086/338190]
Kielar, C., Wishart, T. M., Palmer, A., Dihanich, S., Wong, A. M., Macauley, S. L., Chan, C.-H., Sands, M. S., Pearce, D. A., Cooper, J. D., Gillingwater, T. H. Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. Hum. Molec. Genet. 18: 4066-4080, 2009. [PubMed: 19640925] [Full Text: https://doi.org/10.1093/hmg/ddp355]
Moore, S. J., Buckley, D. J., MacMillan, A., Marshall, H. D., Steele, L., Ray, P. N., Nawaz, Z., Baskin, B., Frecker, M., Carr, S. M., Ives, E., Parfrey, P. S. The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland. Clin. Genet. 74: 213-222, 2008. [PubMed: 18684116] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01054.x]
Sharp, J. D., Wheeler, R. B., Parker, K. A., Gardiner, R. M., Williams, R. E., Mole, S. E. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 22: 35-42, 2003. [PubMed: 12815591] [Full Text: https://doi.org/10.1002/humu.10227]
Siintola, E., Topcu, M., Kohlschutter, A., Salonen, T., Joensuu, T., Anttonen, A.-K., Lehesjoki, A.-E. Two novel CLN6 mutations in variant late-infantile neuronal ceroid lipofuscinosis patients of Turkish origin. Clin. Genet. 68: 167-173, 2005. [PubMed: 15996215] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00471.x]
Teixeira, C. A., Espinola, J., Huo, L., Kohlschutter, J., Persaud Sawin, D.-A., Minassian, B., Bessa, C. J. P., Guimaraes, A., Stephan, D. A., Sa Miranda, M. C., MacDonald, M. E., Gil Ribeiro, M., Boustany, R.-M. N. Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 21: 502-508, 2003. [PubMed: 12673792] [Full Text: https://doi.org/10.1002/humu.10207]
Wheeler, R. B., Sharp, J. D., Schultz, R. A., Joslin, J. M., Williams, R. E., Mole, S. E. The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am. J. Hum. Genet. 70: 537-542, 2002. [PubMed: 11727201] [Full Text: https://doi.org/10.1086/338708]