Alternative titles; symbols
HGNC Approved Gene Symbol: CLN5
Cytogenetic location: 13q22.3 Genomic coordinates (GRCh38) : 13:76,992,081-77,005,117 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q22.3 | Ceroid lipofuscinosis, neuronal, 5 | 256731 | Autosomal recessive | 3 |
Savukoski et al. (1998) reported positional cloning of the CLN5 gene, which encodes a putative 407-amino acid transmembrane protein. Northern blot analysis showed relatively weak hybridization signals of approximately 2.0, 3.0, and 4.5 kb in all human tissues tested. Additionally, a 5.5-kb signal was seen in skeletal muscle. Overall observation suggested expression of CLN5 in all human tissues, with up to 5-fold variation in expression levels.
By immunofluorescence microscopy, Isosomppi et al. (2002) demonstrated that wildtype CLN5 is predominantly targeted to lysosomes. Immunoprecipitation analysis recognized a 60-kD polypeptide, which was reduced to 38-40 kD by deglycosylation. Glycosylated polypeptides were also observed in the media, suggesting that the CLN5 polypeptide may represent a soluble lysosomal glycoprotein, rather than an integral transmembrane protein as predicted previously.
Larkin et al. (2013) identified 2 hydrophobic regions predicted to function as transmembrane domains near the N and C termini of CLN5, a signal peptide cleavage site following the putative N-terminal transmembrane domain, and 8 putative N-glycosylation sites. However, protease digestion, extraction, and solubilization experiments performed on CLN5 expressed in HeLa and HEK293 cells revealed that the C-terminal hydrophobic region adopts an amphipathic helix formation and is not a transmembrane domain. The findings suggested a model where CLN5 is synthesized as a precursor with a transmembrane domain near its N terminus. CLN5 is rapidly glycosylated and cleaved at the signal cleavage site after the transmembrane domain, resulting in a mature CLN5 protein located entirely within the lumen of the intracellular compartments. The amphipathic helix near the C terminus mediates tight association of the mature glycosylated protein with intraluminal membranes.
By in vitro studies in COS-1 and HeLa cells, Schmiedt et al. (2010) found that the CLN5 protein is proteolytically cleaved in the endoplasmic reticulum (ER), and that the mature soluble protein is transported to lysosomes in a manner independent of the mannose-6-phosphate mechanism. The protein is highly glycosylated.
Savukoski et al. (1998) determined that the CLN5 gene contains 4 exons.
Gross (2014) mapped the CLN5 gene to chromosome 13q22.3 based on an alignment of the CLN5 sequence (GenBank BC146274) with the genomic sequence (GRCh37).
In patients with neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Savukoski et al. (1998) identified 3 different homozygous mutations in the CLN5 gene (608102.0001-608102.0003).
Isosomppi et al. (2002) noted that the most common CLN5 mutation among patients with the Finnish variant of neuronal ceroid lipofuscinosis is a 2-bp deletion, resulting in a truncated protein (608102.0001). Immunofluorescence-based localization of the mutant protein showed defective intracellular lysosomal targeting. The authors suggested that the pathogenesis of this type of CLN5 may be associated with defective lysosomal trafficking and prevention of normal biologic function.
By in vitro studies in cultured cells, Schmiedt et al. (2010) demonstrated that disease-associated CLN5 mutations perturb intracellular trafficking to lysosomes. For example, about 90% of the D279N (608102.0003) mutant was found in the ER, but only 10% made it to lysosomes. The R112H (608102.0004) mutant mainly localized to the ER and possibly to the Golgi apparatus, but was not found in lysosomes. The level of lysosomal targeting did not correlate with disease onset, suggesting that CLN5 may also function outside of lysosomes.
In 10 of 47 non-Finnish patients with a clinical diagnosis of NCL, Xin et al. (2010) identified 14 mutations in the CLN5 gene, including 11 novel mutations (see, e.g., 608102.0006-608102.0008). Twelve of the 20 disease alleles resulted in premature termination of the protein. The findings suggested that CLN5 mutations may be more common than previously believed, can be found in non-Finnish patients, and can be found in patients with later onset.
Larkin et al. (2013) determined that CLN5 with mutations causing loss of its C-terminal amphipathic helix, such as glu352 to ter (E352X; 608102.0005), was not tightly associated with membranes and was degraded. All mutations studied by Larkin et al. (2013) induced relocalization of CLN5 to the ER.
In 2 sibs with neuronal ceroid lipofuscinosis, El Haddad et al. (2012) identified a homozygous truncating mutation in the CLN5 gene (Q232X; 608102.0010). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. The patients had originally been classified as having CLN9 (609055) by Schulz et al. (2004, 2006) who observed that patient fibroblasts showed decreased dihydroceramide synthase activity (see, e.g., CERS1; 606919). Schulz et al. (2006) found that patient cells showed partial correction of growth defects and apoptosis when transfected with CLN8 (607837) and several human ceramide synthase genes, all of which increase dihydroceramide synthase activity. Schulz et al. (2006) concluded that the protein implicated in CLN9 may be a regulator of dihydroceramide synthase. El Haddad et al. (2012) found that CLN5-null cells had increased growth rates and increased apoptosis compared to controls, and these defects could be corrected by transfection with wildtype CLN5. CLN5-null cells also had decreased levels of sphingolipids downstream of ceramide synthase. CLN5-null patient fibroblasts showed absence of ACTG1 (102560) from CERS1 protein complexes as well as absence of ACTG1-bound proteins, including vimentin and several histone proteins, which may have explained the cellular phenotype of growth defects. The findings suggested a possible association of CLN8 with CLN5, such as CLN8 and CLN5 acting in a concerted manner to activate ceramide synthesis.
Kopra et al. (2004) developed a mouse model of neuronal ceroid lipofuscinosis-5 by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5 -/- mice showed loss of vision and accumulation of autofluorescent storage material in CNS and peripheral tissues, without prominent brain atrophy. Electron microscopy of the storage material revealed a mixture of lamellar profiles including fingerprint profiles and curvilinear and rectilinear bodies. Prominent loss of a subset of GABAergic interneurons in several brain areas was also seen. Brain transcript profiling revealed altered expression of several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected, consistent with the hypomyelination seen in the human CLN5 patients. Since the Cln5 -/- mice did not exhibit significant brain atrophy, Kopra et al. (2004) suggested that these mice could serve as a model for studying the molecular processes associated with advanced aging.
In 17 families with the Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5; 256731), Savukoski et al. (1998) identified a homozygous 2-bp deletion in exon 4 of the CLN5 gene, resulting in a tyr392-to-ter (Y392X) substitution. The predicted protein had 391 amino acids instead of the 407 predicted in controls. The mutation was identified in 34 of 36 disease chromosomes, making it the most common CLN5 mutation in Finland. In a high-risk area on the west coast of Finland, a carrier frequency of 1 in 24 was found in 1 community and approximately 1 in 100 in the rest of the area. No carriers were observed among 100 control individuals from elsewhere in Finland.
In a single Finnish family with the Finnish variant late infantile type of neuronal ceroid lipofuscinosis (CLN5; 256731), Savukoski et al. (1998) found homozygosity for a 1517G-A transition in exon 1 of the CLN5 gene, causing a trp75-to-ter (W75X) nonsense change and a predicted protein of only 74 amino acids.
In a Dutch patient with the Finnish variant late infantile type of neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Savukoski et al. (1998) found the only non-Finnish mutation in the CLN5 gene: homozygosity for a 2127G-A transition, causing an asp279-to-asn (D279N) amino acid substitution.
In affected members of a large consanguineous Colombian family with juvenile-onset neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Pineda-Trujillo et al. (2005) identified a homozygous 1627G-A transition in the CLN5 gene, resulting in an arg112-to-his (R112H) substitution. The mutation occurs in a residue conserved among rodent, amphibian, and bird species, and was not identified in 58 control chromosomes. Onset of the disorder was at age 9 years, consistent with juvenile onset. The findings showed that the disorder occurs outside of northern Europe.
In 2 affected members of a family from Newfoundland with neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Moore et al. (2008) identified a homozygous 1054G-T transversion in the CLN5 gene, resulting in a glu352-to-ter (E352X) substitution. The family had originated from the southwest of England.
In a non-Finnish Caucasian patient with late-onset of neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Xin et al. (2010) identified compound heterozygosity for 2 missense mutations in the CLN5 gene: a 377G-A transition in exon 2, resulting in a cys126-to-tyr (C126Y) substitution in a highly conserved residue, and the Y374C mutation (608102.0007). The patient presented at age 17 years with cognitive regression and visual loss, which progressed to seizures and motor difficulties in the following few years.
In 2 unrelated non-Finnish Caucasian patients with late-onset neuronal ceroid lipofuscinosis-5 (CLN5; 256731), Xin et al. (2010) identified a 1121A-G transition in exon 4 of the CLN5 gene, resulting in a tyr374-to-cys (Y374C) substitution in a highly conserved residue. One patient was compound heterozygous for the Y374C and C126Y (608102.0006) mutations, and the other was compound heterozygous for the Y374C mutation and an intragenic deletion of exon 4 (608102.0008), encompassing at least nucleotides 907 to 1094. Both patients had onset of symptoms at age 17 years, with ultimate visual loss, motor difficulties, seizures, and cognitive regression. Xin et al. (2010) postulated that the Y374C mutant protein retains some residual function, which may explain the later onset in these patients.
For discussion of the exon 4 deletion encompassing at least nucleotides 907 to 1094 in the CLN5 gene that was found in compound heterozygous state in a patient with late-onset neuronal ceroid lipofuscinosis-5 (CLN5; 256731) by Xin et al. (2010), see 608102.0007.
In 2 sibs, born of consanguineous Italian parents, with onset of neuronal ceroid lipofuscinosis-5 (CLN5; 256731) in their mid-fifties, Mancini et al. (2015) identified a homozygous c.935G-A transition in the CLN5 gene, resulting in a ser312-to-asn (S312N) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; an unaffected brother was heterozygous for the variant. In vitro functional expression studies in HEK293 cells showed that the mutant protein was abnormally retained in the endoplasmic reticulum and did not reach the lysosome. The mutant protein was also unstable compared to wildtype. The patients had an unusually late onset of symptoms, and presented with cerebellar ataxia and progressive cognitive decline. Mancini et al. (2015) postulated that the S312N variant was a hypomorphic allele.
In 2 sibs with neuronal ceroid lipofuscinosis-5 (CLN5; 256731), El Haddad et al. (2012) identified a homozygous c.694C-T transition in the CLN5 gene, resulting in a gln232-to-ter (Q232X) substitution. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. Western blot analysis of patient fibroblasts confirmed the presence of a truncated CLN5 protein. The patients had previously been reported by Schulz et al. (2004) as having neuronal ceroid lipofuscinosis-9 (CLN9; 609055).
El Haddad, S., Khoury, M., Daoud, M., Kantar, R., Harati, H., Mousallem, T., Alzate, O., Meyer, B., Boustany, R.-M. CLN5 and CLN8 protein association with ceramide synthase: biochemical and proteomic approaches. Electrophoresis 33: 3798-3809, 2012. [PubMed: 23160995] [Full Text: https://doi.org/10.1002/elps.201200472]
Gross, M. B. Personal Communication. Baltimore, Md. 6/4/2014.
Isosomppi, J., Vesa, J., Jalanko, A., Peltonen, L. Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. Hum. Molec. Genet. 11: 885-891, 2002. [PubMed: 11971870] [Full Text: https://doi.org/10.1093/hmg/11.8.885]
Kopra, O., Vesa, J., von Schantz, C., Manninen, T., Minye, H., Fabritius, A.-L., Rapola, J., van Diggelen, O. P., Saarela, J., Jalanko, A., Peltonen, L. A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging. Hum. Molec. Genet. 13: 2893-2906, 2004. [PubMed: 15459177] [Full Text: https://doi.org/10.1093/hmg/ddh312]
Larkin, H., Ribeiro, M. G., Lavoie, C. Topology and membrane anchoring of the lysosomal storage disease-related protein CLN5. Hum. Mutat. 34: 1688-1697, 2013. [PubMed: 24038957] [Full Text: https://doi.org/10.1002/humu.22443]
Mancini, C., Nassani, S., Guo, Y., Chen, Y., Giorgio, E., Brussino, A., Di Gregorio, E., Cavalieri, S., Lo Buono, N., Funaro, A., Pizio, N. R., Nmezi, B., Kyttala, A., Santorelli, F. M., Padiath, Q. S., Hakonarson, H., Zhang, H., Brusco, A. Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations. J. Neurol. 262: 173-178, 2015. [PubMed: 25359263] [Full Text: https://doi.org/10.1007/s00415-014-7553-y]
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]
Pineda-Trujillo, N., Cornejo, W., Carrizosa, J., Wheeler, R. B., Munera, S., Valencia, A., Agudelo-Arango, J., Cogollo, A., Anderson, G., Bedoya, G., Mole, S. E., Ruiz-Linares, A. A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset. Neurology 64: 740-742, 2005. [PubMed: 15728307] [Full Text: https://doi.org/10.1212/01.WNL.0000151974.44980.F1]
Savukoski, M., Klockars, T., Holmberg, V., Santavuori, P., Lander, E. S., Peltonen, L. CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. Nature Genet. 19: 286-288, 1998. [PubMed: 9662406] [Full Text: https://doi.org/10.1038/975]
Schmiedt, M.-L., Bessa, C., Heine, C., Ribeiro, M. G., Jalanko, A., Kyttala, A. The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations. Hum. Mutat. 31: 356-365, 2010. [PubMed: 20052765] [Full Text: https://doi.org/10.1002/humu.21195]
Schulz, A., Dhar, S., Rylova, S., Dbaibo, G., Alroy, J., Hagel, C., Artacho, I., Kohlschutter, A., Lin, S., Boustany, R.-M. Impaired cell adhesion and apoptosis in a novel CLN9 Batten disease variant. Ann. Neurol. 56: 342-350, 2004. [PubMed: 15349861] [Full Text: https://doi.org/10.1002/ana.20187]
Schulz, A., Mousallem, T., Venkataramani, M., Persaud-Sawin, D.-A., Zucker, A., Luberto, C., Bielawska, A., Bielawski, J., Holthuis, J. C. M., Jazwinski, S. M., Kozhaya, L., Dbaibo, G. S., Boustany, R.-M. N. The CLN9 protein, a regulator of dihydroceramide synthase. J. Biol. Chem. 281: 2784-2794, 2006. [PubMed: 16303764] [Full Text: https://doi.org/10.1074/jbc.M509483200]
Xin, W., Mullen, T. E., Kiely, R., Min, J., Feng, X., Cao, Y., O'Malley, L., Shen, Y., Chu-Shore, C., Mole, S. E., Goebel, H. H., Sims, K. CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. Neurology 74: 565-571, 2010. [PubMed: 20157158] [Full Text: https://doi.org/10.1212/WNL.0b013e3181cff70d]