Alternative titles; symbols
HGNC Approved Gene Symbol: DNAJC5
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:63,895,126-63,936,011 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | Ceroid lipofuscinosis, neuronal, 4 (Kufs type), autosomal dominant | 162350 | Autosomal dominant | 3 |
The DNAJC5 gene encodes the cysteine string protein, a presynaptic J protein expressed in neural tissues as well as in synaptic and clathrin-coated vesicles (summary by Cadieux-Dion et al., 2013).
Using antibody directed against rat Csp to screen a brain cDNA expression library, Coppola and Gundersen (1996) obtained a full-length human CSP clone. The deduced 198-amino acid protein differs from rat Csp at only 1 residue. Coppola and Gundersen (1996) also cloned a splice variant of CSP that contains a 72-nucleotide insertion that introduces an in-frame stop codon. This variant encodes a deduced 167-amino acid protein that is identical to the full-length protein for the first 164 amino acids. Northern blot analysis detected at least 3 CSP variants in all 8 human tissues examined. Western blot analysis of human blood detected CSP at an apparent molecular mass of 35 kD. Treatment with a deacylating agent caused a downward shift of 7 kD in apparent mass.
Tobaben et al. (2001) showed that the 198-amino acid rat Csp protein contains an N-terminal J domain, followed by a cysteine string and a C-terminal domain. They noted that most of the cysteines are palmitoylated and are required for membrane targeting of Csp.
Using real-time RT-PCR, Fernandez-Chacon et al. (2004) detected Csp-alpha in mouse brain and testis.
Natochin et al. (2005) stated that rat Csp has 2 binding sites for G proteins, one that overlaps the J domain and binds G-alpha subunits (see GNAS, 139320), and another between the J domain and cysteine string that binds G-beta (see GNB1, 139380) and/or the G-alpha-beta-gamma (see GNG2, 606981) trimer.
Tobaben et al. (2001) showed that rat Csp interacted with Sgt (SGTA; 603419) and Hsc70 (HSPA8; 600816) in a complex located on the synaptic vesicle surface. The complex functioned as an ATP-dependent chaperone that reactivated a denatured substrate. Sgt overexpression in cultured rat hippocampal neurons inhibited neurotransmitter release, suggesting that the Csp/Sgt/Hsc70 complex is important for maintenance of a normal synapse.
Miller et al. (2003) stated that rat Csp binds both the N-type calcium channel (see 601012) and G protein beta-gamma subunits in vitro, and that these associations give rise to tonic G protein inhibition of the calcium channel. They showed that an N-terminal fragment of human huntingtin (HTT; 613004) with an expanded polyglutamine tract blocked association of Csp with G proteins and eliminated Csp's tonic G protein inhibition of N-type calcium channels. In contrast, an N-terminal huntingtin fragment without an expanded polyglutamine tract did not alter association of Csp with G proteins and had no effect on channel inhibition by Csp.
Natochin et al. (2005) showed that rat Csp stimulated GDP/GTP exchange on G-alpha-S. Modulation of G proteins by Csp was, in turn, regulated by Hsc70 and Sgt.
Gross (2011) mapped the DNAJC5 gene to chromosome 20q13.33 based on an alignment of the DNAJC5 sequence (GenBank BC053642) with the genomic sequence (GRCh37).
In a Czech family with an autosomal dominant form of Kufs disease, ceroid neuronal lipofuscinosis-4 (CLN4; 162350), Noskova et al. (2011) identified a heterozygous 3-bp deletion in the DNAJC5 gene (346_348delCTC; 611203.0001), resulting in deletion of leu116. The mutation was found by a combination of linkage analysis, copy-number analysis, gene-expression analysis, and exome sequencing of candidate genes. Screening of this gene in 20 additional families identified pathogenic mutations, including a novel missense mutation (L115R; 611203.0002), in 4. Two of the families had been reported by Josephson et al. (2001) and Nijssen et al. (2002). The patients had onset of rapidly progressive neurodegenerative disorder with onset in the third or fourth decades.
In patients with CLN4, Benitez et al. (2011) and Velinov et al. (2012) found the same 2 heterozygous mutations in the DNAJC5 gene as those reported by Noskova et al. (2011), thus confirming the findings. Benitez et al. (2011) studied the family originally reported by Josephson et al. (2001), and Velinov et al. (2012) studied the Parry family originally reported by Boehme et al. (1971).
By linkage analysis combined with exome sequencing in the large family (Parry family) with adult-onset CLN reported by Boehme et al. (1971), Cadieux-Dion et al. (2013) also identified heterozygosity for the same 3-bp deletion mutation in the DNAJC5 gene (611203.0001). The mutation was confirmed by Sanger sequencing, was not found in 380 control chromosomes, and segregated with the disorder in the family. The American patient reported by Noskova et al. (2011) who carried this mutation was found to be from the Parry family. Cadieux-Dion et al. (2013) also identified the leu116del mutation in affected members of a family from Alabama reported by Burneo et al. (2003). Haplotype analysis did not show a founder effect between the 2 families, suggesting that it is a recurrent mutation. Cadieux-Dion et al. (2013) also identified a heterozygous L115R mutation in the DNAJC5 gene (611203.0002) in 1 of 6 additional patients with the disorder; this patient had no family history. Overall, DNAJC5 mutations accounted for 38% of cases with unexplained adult-onset NCL in their cohort, with the mutations occurring at mutational hotspots.
In 2 Canadian sibs with CLN4, Jedlickova et al. (2020) identified a heterozygous 30-bp duplication in the DNAJC5 gene (c.370_399dup; 611203.0003), resulting in an in-frame duplication involving the central core motif of the cysteine-string domain of the CSP-alpha protein. On initial targeted Sanger sequencing of the DNAJC5 gene, the 30-bp duplication was not identified, likely due to preferential amplification of the wildtype allele and allelic drop out of the mutated allele. Furthermore, the 30-bp duplication was initially missed on whole-exome sequencing and was identified only after exome reanalysis was performed with altered variant detection thresholds. Redesign of Sanger sequencing parameters confirmed the presence of the 30-bp duplication mutant. Expression of the mutant protein in CAD5 cells demonstrated abnormal cellular localization, abnormal palmitoylation, and formation of high molecular weight aggregates.
Fernandez-Chacon et al. (2004) found that Csp-alpha -/- mice appeared normal at birth but developed a progressive lethal phenotype that manifested as muscle weakness and a sensorimotor disorder at 2 to 4 weeks of age. Analysis of synaptic transmission in Csp-alpha -/- neuromuscular junctions and at the Calyx of Held synapse revealed normal Ca(2+) channel function and Ca(2+)-dependent exocytosis. However, synapses showed progressively worsening presynaptic degeneration, with persistent vacuoles, proliferation of multilamellar bodies, and protrusion of Schwann cell fingers into the neuromuscular nerve terminal. Coppola and Gundersen (1996) concluded that the degeneration of Csp-alpha -/- synapses appeared to occur in a use-dependent manner and that CSP-alpha is required to maintain the integrity of synapses in the face of use-dependent stress.
In affected members of a Czech family with an autosomal dominant form of Kufs disease, neuronal ceroid lipofuscinosis-4 (CLN4; 162350), Noskova et al. (2011) identified a heterozygous 3-bp deletion (346_348delCTC) in the DNAJC5 gene, resulting in a deletion of leu116 (Leu116del) in a conserved region of the cysteine-string domain of the protein. Screening of this gene in 20 additional families identified this mutation in 1 affected American patient who had a family history of the disorder. The patients had onset of rapidly progressive neurodegenerative disorder with onset in the third or fourth decades. Haplotype analysis did not suggest a common origin. The mutation was not found in 200 controls. In vitro functional expression in CAD5 neuronal cells showed that the mutant protein had abnormal diffuse intracellular localization and abnormal colocalization with markers for the endoplasmic reticulum and Golgi apparatus. Immunoblot analysis indicated that the mutant protein was less efficiently palmitoylated compared to wildtype. Analysis of brain tissue from affected individuals showed significantly reduced immunostaining for DNAJC5 in the cerebral cortex compared to controls.
Benitez et al. (2011) identified the heterozygous 346_348delCTC mutation in affected members of a family with CLN4. The mutation, which was found by Sanger sequencing, was not present in the dbSNP (build 134) or 1000 Genomes Project databases or in more than 3,200 control chromosomes. These findings confirmed the report of Noskova et al. (2011). Molecular modeling studies predicted that the mutation may weaken membrane binding by decreasing affinity of the protein for the membrane. Other functional studies were not performed.
Velinov et al. (2012) identified the 3-bp deletion mutation in affected members of the original Parry family with CLN4 (Boehme et al., 1971). Affected individuals also carried a heterozygous 1430A-G transition in the PRPF6 gene (613979), resulting in an asn477-to-ser (N477S) substitution at a highly conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in 2,100 control individuals. Both changes occurred within about 75 kb on chromosome 20 and were likely linked on a rare haplotype. Velinov et al. (2012) noted that a PRPF6 mutation has been associated with retinitis pigmentosa-60 (RP60; 613983) and that some members of the Parry family had unspecified visual problems, suggesting that it may be a phenotypic modifier in this family.
By linkage analysis combined with exome sequencing in the large family (Parry family) with adult-onset CLN reported by Boehme et al. (1971), Cadieux-Dion et al. (2013) identified a heterozygous 346_348del mutation. The mutation was confirmed by Sanger sequencing, was not found in 380 control chromosomes, and segregated with the disorder in the family. The American patient reported by Noskova et al. (2011) who carried this mutation was found to be from the Parry family. Cadieux-Dion et al. (2013) also identified the leu116del mutation in affected members of a family from Alabama reported by Burneo et al. (2003), even though the mutation in this family had not been found by Noskova et al. (2011). Haplotype analysis did not show a founder effect between the 2 families, suggesting that it is a recurrent mutation.
In affected members of 2 unrelated families and 1 patient with autosomal dominant Kufs disease (CLN4; 162350), Noskova et al. (2011) identified a heterozygous 344T-G transversion in the DNAJC5 gene, resulting in a leu115-to-arg (L115R) substitution in a conserved residue in the cysteine-string domain of the protein. Two of the families had been reported by Josephson et al. (2001) and Nijssen et al. (2002). The mutation was not found in 200 controls. Haplotype analysis did not suggest a common origin. In vitro functional expression in CAD5 neuronal cells showed that the mutant protein had abnormal diffuse intracellular localization and abnormal colocalization with markers for the endoplasmic reticulum and Golgi apparatus. Immunoblot analysis indicated that the mutant protein was less efficiently palmitoylated compared to wildtype. Analysis of brain tissue from affected individuals showed absence of immunostaining for DNAJC5 in synaptic regions in both the cerebral and cerebellar cortex compared to controls. However, there was some evidence for an insoluble DNAJC5-containing aggregate in brain lysate.
Benitez et al. (2011) identified a heterozygous L115R mutation in affected members of a large family with CLN4 originally reported by Josephson et al. (2001). The mutation, which was found by whole-exome sequencing and filtered against the dbSNP (build 130) and 1000 Genomes Project databases as well as 59 in-house exomes, was confirmed by Sanger sequencing to segregate with the disorder in the family. It was also absent in an additional 1,600 controls. Molecular modeling studies predicted that the mutation may weaken membrane binding by decreasing affinity of the protein for the membrane. Other functional studies were not performed. These findings confirmed the report of Noskova et al. (2011).
Velinov et al. (2012) identified a heterozygous L115R mutation in a patient with CLN4B.
Cadieux-Dion et al. (2013) identified a heterozygous L115R mutation in a patient with sporadic occurrence of CLN4B.
In 2 sibs with autosomal dominant Kufs disease (CLN4; 162350), Jedlickova et al. (2020) identified a heterozygous 30-bp duplication (c.370_399dup, NM_025219.2) in exon 4 of the DNAJC5 gene, resulting in an in-frame duplication (Cys124_Cys133). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The duplication encodes the central core motif of the cysteine-string domain of CSP-alpha. Expression of mutant CSP-alpha in CAD5 cells showed abnormal cellular localization with reduced expression in the plasma membrane, abnormal palmitoylation with only the nonpalmitoylated form present, and formation of high molecular weight aggregates.
Benitez, B. A., Alvarado, D., Cai, Y., Mayo, K., Chakraverty, S., Norton, J., Morris, J. C., Sands, M. S., Goate, A., Cruchaga, C. Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis. PLoS One 6: e26741, 2011. Note: Electronic Article. [PubMed: 22073189] [Full Text: https://doi.org/10.1371/journal.pone.0026741]
Boehme, D. H., Cottrell, J. C., Leonberg, S. C., Zeman, W. A dominant form of neuronal ceroid-lipofuscinosis. Brain 94: 745-760, 1971. [PubMed: 5132971] [Full Text: https://doi.org/10.1093/brain/94.4.745]
Burneo, J. G., Arnold, T., Palmer, C. A., Kuzniecky, R. I., Oh, S. J., Faught, E. Adult-onset neuronal ceroid lipofuscinosis (Kufs disease) with autosomal dominant inheritance in Alabama. Epilepsia 44: 841-846, 2003. [PubMed: 12790899] [Full Text: https://doi.org/10.1046/j.1528-1157.2003.39802.x]
Cadieux-Dion, M., Andermann, E., Lachance-Touchette, P., Ansorge, O., Meloche, C., Barnabe, A., Kuzniecky, R. I., Andermann, F., Faught, E., Leonberg, S., Damiano, J. A., Berkovic, S. F., Rouleau, G. A., Cossette, P. Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease. Clin. Genet. 83: 571-575, 2013. [PubMed: 22978711] [Full Text: https://doi.org/10.1111/cge.12020]
Coppola, T., Gundersen, C. Widespread expression of human cysteine string proteins. FEBS Lett. 391: 269-272, 1996. [PubMed: 8764987] [Full Text: https://doi.org/10.1016/0014-5793(96)00750-8]
Fernandez-Chacon, R., Wolfel, M., Nishimune, H., Tabares, L., Schmitz, F., Castellano-Munoz, M., Rosenmund, C., Montesinos, M. L., Sanes, J. R., Schneggenburger, R., Sudhof, T. C. The synaptic vesicle protein CSP-alpha prevents presynaptic degeneration. Neuron 42: 237-251, 2004. [PubMed: 15091340] [Full Text: https://doi.org/10.1016/s0896-6273(04)00190-4]
Gross, M. B. Personal Communication. Baltimore, Md. 4/28/2011.
Jedlickova, I., Cadieux-Dion, M., Pristoupilova, A., Stranecky, V., Hartmannova, H., Hodanova, K., Baresova, V., Hulkova, H., Sikora, J., Noskova, L., Musalkova, D., Vyletal, P., Sovova, J., Cossette, P., Andermann, E., Andermann, F., Kmoch, S., Adult NCL Gene Discovery Consortium. Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing. Europ. J. Hum. Genet. 28: 783-789, 2020. [PubMed: 31919451] [Full Text: https://doi.org/10.1038/s41431-019-0567-2]
Josephson, S. A., Schmidt, R. E., Millsap, P., McManus, D. Q., Morris, J. C. Autosomal dominant Kufs' disease: a cause of early onset dementia. J. Neurol. Sci. 188: 51-60, 2001. [PubMed: 11489285] [Full Text: https://doi.org/10.1016/s0022-510x(01)00546-9]
Miller, L. C., Swayne, L. A., Chen, L., Feng, Z.-P., Wacker, J. L., Muchowski, P. J., Zamponi, G. W., Braun, J. E. A. Cysteine string protein (CSP) inhibition of N-type calcium channels is blocked by mutant huntingtin. J. Biol. Chem. 278: 53072-53081, 2003. [PubMed: 14570907] [Full Text: https://doi.org/10.1074/jbc.M306230200]
Natochin, M., Campbell, T. N., Barren, B., Miller, L. C., Hameed, S., Artemyev, N. O., Braun, J. E. A. Characterization of the G-alpha-s regulator cysteine string protein. J. Biol. Chem. 280: 30236-30241, 2005. [PubMed: 15972823] [Full Text: https://doi.org/10.1074/jbc.M500722200]
Nijssen, P. C. G., Brusse, E., Leyten, A. C. M., Martin, J. J., Teepen, J. L. J. M., Roos, R. A. C. Autosomal dominant adult neuronal ceroid lipofuscinosis: parkinsonism due to both striatal and nigral dysfunction. Mov. Disord. 17: 482-487, 2002. [PubMed: 12112194] [Full Text: https://doi.org/10.1002/mds.10104]
Noskova, L., Stranecky, V., Hartmannova, H., Pristoupilova, A., Baresova, V., Ivanek, R., Hulkova, H., Jahnova, H., van der Zee, J., Staropoli, J. F., Sims, K. B., Tyynela, J., Van Broeckhoven, C., Nijssen, P. C. G., Mole, S. E., Elleder, M., Kmoch, S. Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am. J. Hum. Genet. 89: 241-252, 2011. Note: Erratum: Am. J. Hum. Genet. 89: 589 only, 2011. [PubMed: 21820099] [Full Text: https://doi.org/10.1016/j.ajhg.2011.07.003]
Tobaben, S., Thakur, P., Fernandez-Chacon, R., Sudhof, T. C., Rettig, J., Stahl, B. A trimeric protein complex functions as a synaptic chaperone machine. Neuron 31: 987-999, 2001. [PubMed: 11580898] [Full Text: https://doi.org/10.1016/s0896-6273(01)00427-5]
Velinov, M., Dolzhanskaya, N., Gonzalez, M., Powell, E., Konidari, I., Hulme, W., Staropoli, J. F., Xin, W., Wen, G. Y., Barone, R., Coppel, S. H., Sims, K., Brown, W. T., Zuchner, S. Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in a proportion of cases: study of the Parry family and 8 other families. PLoS One 7: e29729, 2012. Note: Electronic Article. Erratum published online. [PubMed: 22235333] [Full Text: https://doi.org/10.1371/journal.pone.0029729]