Alternative titles; symbols
HGNC Approved Gene Symbol: CLN8
SNOMEDCT: 703526007;
Cytogenetic location: 8p23.3 Genomic coordinates (GRCh38) : 8:1,753,059-1,786,570 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p23.3 | Ceroid lipofuscinosis, neuronal, 8 | 600143 | Autosomal recessive | 3 |
| Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant | 610003 | Autosomal recessive | 3 |
Ranta et al. (1999) reported the positional cloning of a novel gene, CLN8, in the critical region of chromosome 8p for progressive epilepsy with mental retardation (EPMR; 610003), or Northern epilepsy. The CLN8 gene encodes a deduced 286-amino acid transmembrane protein with a molecular mass of 80 kD. Ranta et al. (1999) also cloned mouse Cln8.
To determine the intracellular localization of CLN8, Lonka et al. (2000) transiently transfected BHK cell lines with CLN8 cDNA. Using CLN8- and cell organelle-specific antibodies with confocal immunofluorescence microscopy, they showed that the CLN8 protein localizes primarily in the ER, with partial localization in the ER-Golgi intermediate compartment (ERGIC). The ER-ERGIC localization was not altered in the CLN8 protein containing a human CLN8 mutation (600143.0001). However, the truncated murine mnd mutant protein was found only in the ER. Mutations in the ER retrieval signal KKRP resulted in localization of CLN8 to the Golgi apparatus. The authors concluded that CLN8 is an ER resident protein that recycles between ER and ERGIC.
Ranta et al. (1999) identified the CLN8 gene within the critical region of chromosome 8p for neuronal ceroid lipofuscinosis-8 (CLN8; 600143). Ranta (1999) stated that the Cln8 gene is located in the centromeric region of mouse chromosome 8p, between markers D8Mit124 and D8Mit61.
Using bimolecular fluorescence complementation (BiFC), Bajaj et al. (2020) demonstrated that Cln8 interacted with Cln6 (606725) in the ER. Cln8 is localized to the ER and the ER-Golgi intermediate compartment, and Cln8 trafficking to the Golgi was found to be uncoupled from its interaction with Cln6. Cln8 and Cln6 were mutually necessary for their interaction with lysosomal enzymes. Cln8 and Cln6 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.
Ranta et al. (1999) found that 22 Finnish patients with the Northern epilepsy variant of CLN8, were homozygous for an arg24-to-gly mutation in the CLN8 gene (607837.0001). The findings indicated a founder effect.
In 9 of 18 families with the so-called Turkish variant of late infantile CLN, Ranta et al. (2004) identified 4 mutations in the CLN8 gene (see 607837.0002-607837.0004), indicating that these patients in fact had CLN8.
In 3 unrelated Italian patients with CLN8, Cannelli et al. (2006) identified homozygous or compound heterozygous mutations in the CLN8 gene (see, e.g., 607837.0005 and 607837.0006, respectively).
Ranta et al. (1999) found conservation of the codon harboring the human CLN8 mutation with the localization of a mutation in the 'motor neuron degeneration' (mnd) mouse, a naturally occurring mouse NCL (Bronson et al., 1993). In mnd/mnd mice, they identified a homozygous 1-bp insertion (267-268insC at codon 90) predicting a frameshift and a truncated protein. This was the first description of the molecular basis of a naturally occurring animal model for NCL.
Katz et al. (2005) identified a leu164-to-pro (L164P) mutation in the Cln8 gene in English setter dogs with autosomal recessive NCL.
In 22 Finnish patients with the Northern epilepsy variant of CLN8 (610003), Ranta et al. (1999) found homozygosity for an arg24-to-gly (R24G) missense mutation which resulted from a C-to-G transversion at nucleotide 70. The carrier frequency was 1 in 135, consistent with a founder mutation.
In affected members of 3 families with the so-called Turkish variant of late infantile CLN, originally reported by Topcu et al. (2004), Ranta et al. (2004) identified homozygosity for a 789G-C transversion in exon 3 of the CLN8 gene, resulting in a trp263-to-cys (W263C) mutation. The findings indicated that these patients in fact had CLN8 (600143). In affected members of another Turkish family reported by Topcu et al. (2004), Ranta et al. (2004) found compound heterozygosity for W263C and R204C (607837.0003).
In affected members of 5 families with the so-called Turkish variant of late infantile CLN, originally reported by Mitchell et al. (2001) and Topcu et al. (2004), Ranta et al. (2004) identified a homozygous 610C-T transition in exon 3 of the CLN8 gene, resulting in an arg204-to-cys (R204C) mutation. The findings indicated that these patients in fact had CLN8 (600143). In affected members of another Turkish family reported by Topcu et al. (2004), Ranta et al. (2004) found compound heterozygosity for R204C and W263C (607837.0002).
In affected members of a family with the so-called Turkish variant of late-infantile CLN, originally reported by Mitchell et al. (2001), Ranta et al. (2004) identified a homozygous 1-bp deletion (88delG) in the CLN8 gene, resulting in a frameshift and premature termination of the protein.
In an Italian child with CLN8 (600143), born of consanguineous parents, Cannelli et al. (2006) identified a homozygous 88G-C transversion in exon 2 of the CLN8 gene, resulting in an ala30-to-pro (A30P) substitution.
In 2 unrelated Italian children with CLN8 (600143), Cannelli et al. (2006) identified compound heterozygosity for 2 mutations in the CLN8 gene: a shared 1-bp deletion (66delG) and a different pathogenic missense mutation in each child. Haplotype analysis of the 66delG mutation suggested a common ancestor.
In an Italian boy with CLN8 (600143), Vantaggiato et al. (2009) identified a homozygous 3-bp deletion (180delGAA) in exon 2 of the CLN8 gene, resulting in the deletion of residue lys61. Further studies showed that the patient had complete isodisomy of maternal chromosome 8. In vitro studies in human neuroblastoma cells and mouse neuronal cells showed that the mutation did not affect protein localization neuronal differentiation, or cellular migration, but did result in increased cellular proliferation that was specific to neuronal cells. Cells with the 180delGAA mutation also showed an increased apoptotic response to NMDA. The findings suggested an indirect role for CLN8 in cell survival.
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]
Bronson, R. T., Lake, B. D., Cook, S., Taylor, S., Davisson, M. T. Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease). Ann. Neurol. 33: 381-385, 1993. [PubMed: 7683855] [Full Text: https://doi.org/10.1002/ana.410330408]
Cannelli, N., Cassandrini, D., Bertini, E., Striano, P., Fusco, L., Gaggero, R., Specchio, N., Biancheri, R., Vigevano, F., Bruno, C., Simonati, A., Zara, F., Santorelli, F. M. Novel mutations in CLN8 in Italian variant late infantile neuronal ceroid lipofuscinosis: another genetic hit in the Mediterranean. Neurogenetics 7: 111-117, 2006. [PubMed: 16570191] [Full Text: https://doi.org/10.1007/s10048-005-0024-y]
Katz, M. L., Khan, S., Awano, T., Shahid, S. A., Siakotos, A. N., Johnson, G. S. A mutation in the CLN8 gene in English setter dogs with neuronal ceroid-lipofuscinosis. Biochem. Biophys. Res. Commun. 327: 541-547, 2005. [PubMed: 15629147] [Full Text: https://doi.org/10.1016/j.bbrc.2004.12.038]
Lonka, L., Kyttala, A., Ranta, S., Jalanko, A., Lehesjoki, A.-E. The neuronal ceroid lipofuscinosis CLN8 membrane protein is a resident of the endoplasmic reticulum. Hum. Molec. Genet. 9: 1691-1697, 2000. [PubMed: 10861296] [Full Text: https://doi.org/10.1093/hmg/9.11.1691]
Mitchell, W. A., Wheeler, R. B., Sharp, J. D., Bate, S. L., Gardiner, R. M., Ranta, U. S., Lonka, L., Williams, R. E., Lehesjoki, A.-E., Mole, S. E. Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8. Europ. J. Paediat. Neurol. 5 (suppl. A): 21-27, 2001. [PubMed: 11589000] [Full Text: https://doi.org/10.1053/ejpn.2000.0429]
Ranta, S., Topcu, M., Tegelberg, S., Tan, H., Ustubutun, A., Saatci, I., Dufke, A., Enders, H., Pohl, K., Alembik, Y., Mitchell, W. A., Mole, S. E., Lehesjoki, A.-E. Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy. Hum. Mutat. 23: 300-305, 2004. [PubMed: 15024724] [Full Text: https://doi.org/10.1002/humu.20018]
Ranta, S., Zhang, Y., Ross, B., Lonka, L., Takkunen, E., Messer, A., Sharp, J., Wheeler, R., Kusumi, K., Mole, S., Liu, W., Soares, M. B., de Fatima Bonaldo, M., Hirvasniemi, A., de la Chapelle, A., Gilliam, T. C., Lehesjoki, A.-E. The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nature Genet. 23: 233-236, 1999. [PubMed: 10508524] [Full Text: https://doi.org/10.1038/13868]
Ranta, S. Personal Communication. Helsinki, Finland 10/1/1999.
Topcu, M., Tan, H., Yalnizoglu, D., Usubutun, A., Saatci, I., Aynaci, M., Anlar, B., Topaloglu, H., Turanli, G., Kose, G., Aysun, S. Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies. Turk. J. Pediat. 46: 1-10, 2004. [PubMed: 15074367]
Vantaggiato, C., Redaelli, F., Falcone, S., Perrotta, C, Tonelli, A., Bondioni, S., Morbin, M., Riva, D., Saletti, V., Bonaglia, M. C., Giorda, R., Bresolin, N., Clementi, E., Bassi, M. T. A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function. Hum. Mutat. 30: 1104-1116, 2009. [PubMed: 19431184] [Full Text: https://doi.org/10.1002/humu.21012]