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HGNC Approved Gene Symbol: CLTC
Cytogenetic location: 17q23.1 Genomic coordinates (GRCh38): 17:59,619,895-59,696,956 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.1 | Intellectual developmental disorder, autosomal dominant 56 | 617854 | Autosomal dominant | 3 |
Clathrin is a major protein component of the cytoplasmic face of intracellular organelles, called coated vesicles and coated pits. These specialized organelles are involved in the intracellular trafficking of receptors and endocytosis of a variety of macromolecules. Clathrin molecules have a triskelion structure composed of 3 noncovalently bound heavy chains (CLTC) and 3 light chains (e.g., CLTA; 118960) (Dodge et al., 1991).
Dodge et al. (1991) isolated a 916-bp cDNA for the heavy chain of clathrin.
DeMari et al. (2016) noted that CLTC is highly expressed in the brain and plays a role in neuronal transmission by facilitating the recycling and/or release of vesicles at the presynaptic termini of neurons.
Huntingtin-interacting protein 1 (HIP1; 601767) is enriched in membrane-containing cell fractions and has been implicated in vesicle trafficking. It is a multidomain protein containing an epsin (607262) N-terminal homology (ENTH) domain, a central coiled-coil-forming region, and a C-terminal actin-binding domain. Waelter et al. (2001) identified 3 HIP1-associated proteins, clathrin heavy chain and alpha-adaptin A and C (AP2A1; 601026). In vitro binding studies revealed that the central coiled-coil domain of HIP1 is required for the interaction with clathrin, whereas DPF-like motifs located upstream to this domain are important for HIP1 binding to the C-terminal 'appendage' domain of alpha-adaptin A and C. Expression of full-length HIP1 in mammalian cells resulted in a punctate cytoplasmic immunostaining characteristic of clathrin-coated vesicles. In contrast, when a truncated HIP1 protein containing both the DPF-like motifs and the coiled-coil domain was overexpressed, large perinuclear vesicle-like structures containing HIP1, huntingtin (613004), clathrin, and endocytosed transferrin were observed, suggesting that HIP1 is an endocytic protein, the structural integrity of which may be crucial for maintenance of normal vesicle size in vivo.
Royle et al. (2005) showed that clathrin stabilizes fibers of the mitotic spindle to aid congression of chromosomes. Clathrin bound to the spindle directly by the N-terminal domain of clathrin heavy chain. Depletion of clathrin heavy chain using RNA interference prolonged mitosis; kinetochore fibers were destabilized, leading to defective congression of chromosomes to the metaphase plate and persistent activation of the spindle checkpoint. Normal mitosis was rescued by clathrin triskelia but not the N-terminal domain of clathrin heavy chain, indicating that stabilization of kinetochore fibers was dependent on the unique structure of clathrin.
Enari et al. (2006) found that CHC localized to both cytosol and nuclei in several human cell lines. Immunoprecipitation analysis showed that CHC interacted directly with p53 (TP53; 191170). CHC overexpression enhanced p53-dependent transactivation, whereas reduction of CHC expression by RNA interference attenuated p53 transcriptional activity. CHC bound to a p53-responsive promoter in vivo and stabilized the interaction between p53 and p300 (EP300; 602700) to promote p53-mediated transcription. Binding of p300 and p53 increased in a CHC dose-dependent manner, and CHC formed a complex with p53 and p300 in response to DNA damage. Clathrin light chains were absent from nuclear CHC-p53 complexes, and CLTA or CLTB (118970) blocked p53-CHC associations in vitro by sequestering CHC. Enari et al. (2006) hypothesized that CHC recruits p300 and p53 to p53-responsive promoters and may function as a scaffold protein bridging p53 and p300.
Deborde et al. (2008) showed that clathrin is required for polarity of the basolateral plasma membrane proteins in the epithelial cell line MDCK. Clathrin knockdown depolarized most basolateral proteins, by interfering with their biosynthetic delivery and recycling, but did not affect the polarity of apical proteins. Quantitative live imaging showed that chronic and acute clathrin knockdown selectively slowed down the exit of basolateral proteins from the Golgi complex, and promoted their missorting into apical carrier vesicles. Deborde et al. (2008) concluded that their results demonstrated a broad requirement for clathrin in basolateral protein trafficking in epithelial cells.
Crystal Structure
Fotin et al. (2004) reported the structure of a clathrin lattice at subnanometer resolution, obtained from electron cryomicroscopy of clathrin coats assembled in vitro. They traced most of the 1,675-residue clathrin heavy chain by fitting known crystal structures of 2 segments, and homology models of the rest, into the electron microscopy density map. They also defined the position of the central helical segment of the light chain. A helical tripod, the carboxy-terminal parts of 3 heavy chains, projects inward from the vertex of each 3-legged clathrin triskelion, linking that vertex to 'ankles' of triskelions centered 2 vertices away. Analysis of coats with distinct diameters showed an invariant pattern of contacts in the neighborhood of each vertex, with more variable interactions along the extended parts of the triskelion 'legs.' These invariant local interactions appear to stabilize the lattice, allowing assembly and uncoating to be controlled by events at a few specific sites.
Fotin et al. (2004) used electron cryomicroscopy to determine the 12-angstrom resolution structures of in vitro-assembled clathrin coats in association with a C-terminal fragment of auxilin (608375) that contains both the clathrin-binding region and the J domain. They located the auxilin fragment by computing differences between these structures and those lacking auxilin. Auxilin binds within the clathrin lattice near contacts between inward-projecting C-terminal helical tripod and the crossing of 2 'ankle' segments; it also contacts the terminal domain of yet another clathrin 'leg.' Auxilin therefore recruits HSC70 (600816) to the neighborhood of a set of critical interactions. Auxilin binding produces a local change in heavy-chain contacts, creating a detectable global distortion of the clathrin coat. Fotin et al. (2004) proposed a mechanism by which local destabilization of the lattice promotes general uncoating.
By Southern analysis of human/rodent somatic cell hybrids, Dodge et al. (1991) localized the CLTC gene to chromosome 17. Additional analyses using panels of human/rodent somatic cell hybrids with specific chromosomal translocations and deletions mapped the human clathrin heavy chain gene to 17q11-qter.
In the course of comparative mapping of the human 22q11 region in mice, Puech et al. (1997) found that the mouse clathrin D gene (CLTD; 601273), which lies in the center of a cluster of genes whose homologs reside on mouse chromosome 16, is not located there. A gene they referred to as Cltd-rs-4 was located in the central region of mouse chromosome 11 that shares a large region of homology with human chromosome 17. Human CLTC, which is 84.7% identical to CLTD, maps to 17q11-qter. Puech et al. (1997) interpreted their findings as suggesting that in mouse either Cltc and Cltd are tandemly duplicated loci that map to the central region of mouse chromosome 11 or that the mouse genome does not contain a gene corresponding to human CLTD. They favored the latter hypothesis.
Argani et al. (2003) reported a case of renal cell carcinoma (RCCX1; 300854) in which the 5-prime exons of the CLTC gene were fused with the 3-prime exons of the TFE3 gene (314310) as a result of a translocation, t(X;17)(p11.2;q23). The patient was a 14-year-old boy who presented with gross hematuria and was found by CT to have a finely calcified left renal mass.
In a patient with ALK (105590)-negative inflammatory myofibroblastic tumors and an unknown karyotype, Cools et al. (2002) identified fusion of exons of the CLTC gene to exons of the ALK gene from chromosome 2p23. The predicted fusion protein contains 1,634 N-terminal amino acids of CLTC fused to 562 amino acids of ALK, including the ALK kinase domain.
In a 3.5-year-old girl, conceived by in vitro fertilization, with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), DeMari et al. (2016) identified a de novo heterozygous frameshift mutation in the CLTC gene (118955.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated haploinsufficiency of CLTC as the pathogenetic mechanism. DeMari et al. (2016) noted that CLTC plays a role in neuronal transmission by facilitating the recycling and/or release of vesicles at the presynaptic termini of neurons.
Balci et al. (2020) studied the patient reported by DeMari et al. (2016), who was then aged 6 years. She had lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphocytic leukemia. She was found to have a recurrent heterozygous mutation in the DNMT3A gene (R882C; 602769.0007) seen in patients with Tatton-Brown-Rahman syndrome (TBRS; 615879).
In 12 unrelated patients with MRD56, Hamdan et al. (2017) identified de novo heterozygous missense mutations in the CLTC gene (see, e.g., 118955.0002-118955.0006). The mutations were found by whole-exome or whole-genome sequencing of several cohorts of patients with developmental delay and epilepsy. There were 5 truncating mutations, 2 small in-frame deletions, 1 splice site mutation, and 3 missense mutations, 1 of which was recurrent and found in 3 unrelated patients. Individuals with refractory epilepsy were found to carry variants in the first section of the clathrin light chain-binding domain, whereas truncating mutations affecting the C terminus tended to be associated with hypotonia, global developmental delay, and intellectual disability. Studies of patient cells and functional studies of the variants were not performed. Hamdan et al. (2017) noted that CLTC is involved in endocytosis, intracellular trafficking, and synaptic recycling.
In a 3.5-year-old girl, conceived by in vitro fertilization, with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), DeMari et al. (2016) identified a de novo heterozygous 2-bp duplication (c.2737_2738dupGA, NM_004859) in exon 17 of the CLTC gene, predicted to result in a frameshift and premature termination (Asp913GlufsTer59). The mutation was also predicted to result in nonsense-mediated mRNA decay and a complete loss of function. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, Exome Sequencing Project, or 1000 Genomes Project databases. Functional studies of the variant and studies of patient cells were not performed.
Balci et al. (2020) studied the patient reported by DeMari et al. (2016), who was then aged 6 years. She had lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphocytic leukemia. She was found to have a recurrent heterozygous mutation in the DNMT3A gene (R882C; 602769.0007) seen in patients with Tatton-Brown-Rahman syndrome (TBRS; 615879).
In a 23-year-old woman (patient HSC0054) with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), Hamdan et al. (2017) identified a de novo heterozygous 1-bp duplication (c.4575dupA, NM_004859.3) in the CLTC gene, predicted to result in a frameshift and premature termination (Glu1526ArgfsTer18) in the clathrin light chain-binding domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed.
In an 11-year-old girl (patient PBSD) with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), Hamdan et al. (2017) identified a de novo heterozygous 4-bp deletion (c.977_980delCAGT, NM_004859.3) in the CLTC gene, predicted to result in a frameshift and premature termination (Ser326CysfsTer8) in the N-globular domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed.
In 3 unrelated patients (patients indvAA, CAUSES1, and 18052017) with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), Hamdan et al. (2017) identified a de novo heterozygous c.2669C-T transition (c.2669C-T, NM_004859.3) in the CLTC gene, predicted to result in a pro890-to-leu (P890L) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed.
In a 16-year-old boy (patient indvPAR) with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), Hamdan et al. (2017) identified a de novo heterozygous c.3140T-C transition (c.3140T-C, NM_004859.3) in the CLTC gene, predicted to result in a leu1047-to-pro (L1047P) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed.
In a 6-year-old girl (patient DDD0280) with autosomal dominant intellectual developmental disorder-56 (MRD56; 617854), Hamdan et al. (2017) identified a de novo heterozygous c.4663C-T transition (c.4663C-T, NM_004859.3) in the CLTC gene, predicted to result in a gln1555-to-ter (Q1555X) substitution in the trimerization domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed.
Argani, P., Lui, M. Y., Couturier, J., Bouvier, R., Fournet, J.-C., Ladanyi, M. A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 22: 5374-5378, 2003. [PubMed: 12917640] [Full Text: https://doi.org/10.1038/sj.onc.1206686]
Balci, T. B., Strong, A., Kalish, J. M., Zackai, E., Maris, J. M., Reilly, A., Surrey, L. F., Werthei, G. B., Marcadier, J. L., Graham, G. E., Carter, M. T. Tatton-Brown-Rahman syndrome: six individuals with novel features. Am. J. Med. Genet. 182A: 673-680, 2020. [PubMed: 31961069] [Full Text: https://doi.org/10.1002/ajmg.a.61475]
Cools, J., Wlodarska, I., Somers, R., Mentens, N., Pedeutour, F., Maes, B., De Wolf-Peeters, C., Pauwels, P., Hagemeijer, A., Marynen, P. Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 34: 354-362, 2002. [PubMed: 12112524] [Full Text: https://doi.org/10.1002/gcc.10033]
Deborde, S., Perret, E., Gravotta, D., Deora, A., Salvarezza, S., Schreiner, R., Rodriguez-Boulan, E. Clathrin is a key regulator of basolateral polarity. Nature 452: 719-723, 2008. [PubMed: 18401403] [Full Text: https://doi.org/10.1038/nature06828]
DeMari, J., Mroske, C., Tang, S., Nimeh, J., Miller, R., Lebel, R. R. CLTC as a clinically novel gene associated with multiple malformations and developmental delay. Am. J. Med. Genet. 170A: 958-966, 2016. [PubMed: 26822784] [Full Text: https://doi.org/10.1002/ajmg.a.37506]
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Enari, M., Ohmori, K., Kitabayashi, I., Taya, Y. Requirement of clathrin heavy chain for p53-mediated transcription. Genes Dev. 20: 1087-1099, 2006. [PubMed: 16618797] [Full Text: https://doi.org/10.1101/gad.1381906]
Fotin, A., Cheng, Y., Grigorieff, N., Walz, T., Harrison, S. C., Kirchhausen, T. Structure of an auxilin-bound clathrin coat and its implications for the mechanism of uncoating. Nature 432: 649-653, 2004. [PubMed: 15502813] [Full Text: https://doi.org/10.1038/nature03078]
Fotin, A., Cheng, Y., Sliz, P., Grigorieff, N., Harrison, S. C., Kirchhausen, T., Walz, T. Molecular model for a complete clathrin lattice from electron cryomicroscopy. Nature 432: 573-579, 2004. [PubMed: 15502812] [Full Text: https://doi.org/10.1038/nature03079]
Hamdan, F. F., Myers, C. T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A. D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., and 95 others. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am. J. Hum. Genet. 101: 664-685, 2017. [PubMed: 29100083] [Full Text: https://doi.org/10.1016/j.ajhg.2017.09.008]
Puech, A., Saint-Jore, B., Funke, B., Gilbert, D. J., Sirotkin, H., Copeland, N. G., Jenkins, N. A., Kucherlapati, R., Morrow, B., Skoultchi, A. I. Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc. Nat. Acad. Sci. 94: 14608-14613, 1997. [PubMed: 9405660] [Full Text: https://doi.org/10.1073/pnas.94.26.14608]
Royle, S. J., Bright, N. A., Lagnado, L. Clathrin is required for the function of the mitotic spindle. Nature 434: 1152-1157, 2005. [PubMed: 15858577] [Full Text: https://doi.org/10.1038/nature03502]
Waelter, S., Scherzinger, E., Hasenbank, R., Nordhoff, E., Lurz, R., Goehler, H., Gauss, C., Sathasivam, K., Bates, G. P., Lehrach, H., Wanker, E. E. The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis. Hum. Molec. Genet. 10: 1807-1817, 2001. [PubMed: 11532990] [Full Text: https://doi.org/10.1093/hmg/10.17.1807]