Alternative titles; symbols
HGNC Approved Gene Symbol: CLTCL1
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:19,179,473-19,291,719 (from NCBI)
The CLTCL1 gene encodes the minor clathrin heavy chain (CHC22), which is thought to be involved in intracellular endosomal trafficking (summary by Nahorski et al., 2015).
Using a YAC clone containing the velocardiofacial syndrome (VCFS; 192430) critical region on chromosome 22q11 as a substrate for cDNA selection, Sirotkin et al. (1996) derived a cDNA, which they designated CLTD, that encodes a protein with a high degree of homology at the amino acid level to human rat and Drosophila clathrin heavy chain. The CLTD protein is 7% divergent at the amino acid level from that of the human clathrin heavy chain gene (CLTC; 118955) located on chromosome 17q11-qter.
Kedra et al. (1996) cloned and characterized a clathrin heavy chain gene, which they referred to as CLH22. The gene was cloned using a software-based exon-trapping approach based on sequencing of genomic DNA present in chromosome 22q11 contigs combined with the use of exon-prediction computer programs. The 5,470-bp sequence covering the entire open reading frame encodes a 1,640-amino acid polypeptide that is identical to the polypeptide described by Sirotkin et al. (1996). Although expression of the CLTD gene was ubiquitous, it was relatively low in all tissues except skeletal muscle, testis, and heart. The main transcript was 6 kb, and alternate transcripts were detected in several tissues. Kedra et al. (1996) demonstrated loss of expression of the CLTD gene in 37 out of 46 sporadic meningiomas examined. In genomic DNA from 82 sporadic meningiomas, they demonstrated aberrant restriction patterns consistent with intragenic rearrangements in 4 tumors. Based on these findings, the authors proposed that CLTD may be considered a candidate meningioma tumor suppressor gene.
Long et al. (1996) cloned and characterized a gene they symbolized CLTCL for 'CLTC-like.' The gene was expressed in all fetal tissues tested and was selectively expressed in certain adult tissues, particularly skeletal muscle. They observed alternative splicing of an exon near the C terminus of the predicted polypeptide.
Intracellular trafficking of the glucose transporter GLUT4 (138190) from storage compartments to the plasma membrane is triggered in muscle and fat during the body's response to insulin. Clathrin is involved in intracellular trafficking, and in humans, the clathrin heavy-chain isoform CHC22 is highly expressed in skeletal muscle. Vassilopoulos et al. (2009) found a role for CHC22 in the formation of insulin-responsive GLUT4 compartments in human muscle and adipocytes. CHC22 also associated with expanded GLUT4 compartments in muscle from patients with type 2 diabetes (125853). Tissue-specific introduction of CHC22 in mice, which have only a pseudogene for this protein, caused aberrant localization of GLUT4 transport pathway components in their muscle, as well as features of diabetes. Thus, Vassilopoulos et al. (2009) concluded that CHC22-dependent membrane trafficking constitutes a species-restricted pathway in human muscle and fat with potential implications for type 2 diabetes.
By analysis of a transcriptional database, Nahorski et al. (2015) found that CLTCL1 had a peak of expression in the developing human brain between 12 and 13 weeks post-conception, which then dropped by early childhood. Cultured peripheral neurons and neural crest cells showed a downregulation of CLTCL1 during differentiation and neurite outgrowth. Knockdown of CLTCL1 induced neurite outgrowth in neural precursor cells, which was rescued by stable overexpression of small interfering RNA-resistant CLTCL1. Similarly, overexpression of wildtype CLTCL1 blocked neurite outgrowth in cells treated with retinoic acid. These results showed an essential role for CLTCL1 in neural crest development and in the genesis of pain and touch sensing neurons.
Long et al. (1996) used fluorescence in situ hybridization to map CLTCL to proximal 22q near the region commonly deleted in DiGeorge syndrome (DGS; 188400) and VCFS.
In the course of comparative mapping of the human 22q11 region in mice, Puech et al. (1997) found that CLTCL gene, which lies in the center of a cluster of genes whose homologs reside on chromosome 16, is not located there in the mouse. 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. A second human clathrin heavy chain gene, CLTC, which is 84.7% identical to CLTD, maps to 17q11-qter. Puech et al. (1997) interpreted their findings as suggesting that 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.
Holmes et al. (1997) reported characterization of a balanced translocation t(21;22)(p12;q11) within the minimal DiGeorge syndrome critical region in a patient with some features of DGS/VCFS, including facial dysmorphia, mental retardation, long slender digits, and genital anomalies (first-degree hypospadias and bilateral cryptorchidism). Holmes et al. (1997) cloned the breakpoint of the translocation and showed that it interrupted the CLTCL gene within the DGCR. The breakpoint of the translocation partner was in a repeated region telomeric to the rDNA cluster on chromosome 21p, making it unlikely that the patient's findings were caused by interruption of sequences on 21p. The chromosome 22 breakpoint, on the other hand, disrupted the 3-prime coding region of the CLTCL gene and led to a truncated transcript.
Associations Pending Confirmation
For discussion of a possible association between variation in the CLTCL1 gene and congenital inability to feel pain and mental retardation, see 601273.0001.
This variant is classified as a variant of unknown significance because its contribution to congenital inability to feel pain and mental retardation has not been confirmed.
In 3 sibs, born of consanguineous parents of Balochi Iranian origin, with congenital inability to feel pain and severe mental retardation, Nahorski et al. (2015) identified a homozygous c.988G-A transition in exon 7 of the CLTCL1 gene, resulting in a glu330-to-lys (E330K) substitution at a conserved residue at the C terminus of the 7-bladed WD repeat-containing beta-propeller that forms the adaptor binding domain of the clathrin heavy chains. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project database or in 360 control chromosomes. Transfection of the mutation into HEK293 cells and E. coli showed that the mutant protein was expressed and that the mutation did not affect folding of the clathrin N-terminal beta-propeller domain; however, the mutant protein was unable to rescue a cellular defect in clathrin-mediated endocytosis. Knockdown of CLTCL1 induced neurite outgrowth in neural precursor cells, which was rescued by stable overexpression of small interfering RNA-resistant CLTCL1, but not by mutant CLTCL1. Similarly, overexpression of wildtype, but not mutant, CLTCL1 blocked neurite outgrowth in cells treated with retinoic acid. The findings suggested that the mutant protein was unable to function normally as a negative regulator of sensory neuron differentiation. The patients were unable to sense pain from birth and were unresponsive to soft touch. All also had developmental delay with severe learning difficulties. Motor movements and strength were normal, and hot and cold could be perceived. More variable features included dysmorphic facies, rocker-bottom feet, poor or absent vision, abnormal eye movements, seizures, and corneal keratitis. Brain imaging of 2 patients suggested delayed myelination. Two patients died in childhood; the third was alive with severe global developmental delay at age 5 years. Because electrophysiologic studies and skin and nerve biopsy were declined by the parents, the etiology of the sensory deficiency could not be accurately assessed. The clinical features suggested both peripheral and central nervous system involvement.
Holmes, S. E., Riazi, M. A., Gong, W., McDermid, H. E., Sellinger, B. T., Hua, A., Chen, F., Wang, Z., Zhang, G., Roe, B., Gonzalez, I., McDonald-McGinn, D. M., Zackai, E., Emanuel, B. S., Budarf, M. L. Disruption of the clathrin heavy chain-like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation. Hum. Molec. Genet. 6: 357-367, 1997. [PubMed: 9147638] [Full Text: https://doi.org/10.1093/hmg/6.3.357]
Kedra, D., Peyrard, M., Fransson, I., Collins, J. E., Dunham, I., Roe, B. A., Dumanski, J. P. Characterization of a second human clathrin heavy chain polypeptide gene (CLH-22) from chromosome 22q11. Hum. Molec. Genet. 5: 625-631, 1996. [PubMed: 8733129] [Full Text: https://doi.org/10.1093/hmg/5.5.625]
Long, K. R., Trofatter, J. A., Ramesh, V., McCormick, M. K., Buckler, A. J. Cloning and characterization of a novel human clathrin heavy chain gene (CLTCL). Genomics 35: 466-472, 1996. [PubMed: 8844170] [Full Text: https://doi.org/10.1006/geno.1996.0386]
Nahorski, M. S., Al-Gazali, L., Hertecant, J., Owen, D. J., Borner, G. H. H., Chen, Y.-C., Benn, C. L., Carvalho, O. P., Shaikh, S. S., Phelan, A., Robinson, M. S., Royle, S. J., Woods, C. G. A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development. Brain 138: 2147-2160, 2015. [PubMed: 26068709] [Full Text: https://doi.org/10.1093/brain/awv149]
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]
Sirotkin, H., Morrow, B., DasGupta, R., Goldberg, R., Patanjali, S. R., Shi, G., Cannizzaro, L., Shprintzen, R., Weissman, S. M., Kucherlapati, R. Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome. Hum. Molec. Genet. 5: 617-624, 1996. [PubMed: 8733128] [Full Text: https://doi.org/10.1093/hmg/5.5.617]
Vassilopoulos, S., Esk, C., Hoshino, S., Funke, B. H., Chen, C.-Y., Plocik, A. M., Wright, W. E., Kucherlapati, R., Brodsky, F. M. A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism. Science 324: 1192-1196, 2009. [PubMed: 19478182] [Full Text: https://doi.org/10.1126/science.1171529]