Alternative titles; symbols
HGNC Approved Gene Symbol: CHL1
Cytogenetic location: 3p26.3 Genomic coordinates (GRCh38) : 3:196,763-409,417 (from NCBI)
To identify genes contributing to mental retardation in patients with 3p- syndrome (613792), Wei et al. (1998) used in silico searches for neural genes in sequence databases. They obtained an EST with strong homology to the rat Caml1 gene (L1CAM; 308840) and used it to isolate a full-length cDNA encoding CHL1, which the authors designated CALL. Molecular analysis of CALL showed that it is a novel member of the L1 gene family of neural cell adhesion molecules. The predicted CALL protein contains 1,224 amino acids and has a calculated molecular mass of 136 kD. It has a signal peptide, followed by 6 immunoglobulin (Ig) domains, 4 fibronectin (see 135600) type III (FNIII) domains, a single-pass transmembrane peptide, and a 105-amino acid cytoplasmic domain. The cytoplasmic domain of CALL is conserved among other members of the L1 subfamily and features sequence motifs that may involve CALL in signal transduction pathways. The CALL protein has 21 potential N-glycosylation sites, more than 50 O-glycosylation sites, 22 N-myristoylation sites, 2 amidation sites, and multiple phosphorylation sites. CALL shares 84% amino acid identity with the mouse Chl1 protein, and both proteins have the same domain structure and membrane topology, as well as similar expression patterns. Wei et al. (1998) confirmed the orthology of CALL and Chl1 by phylogenetic analysis. Northern blot analysis and EST representation revealed that CALL is expressed in brain and also outside the nervous system in some adult human tissues and tumor cell lines. CALL was expressed predominantly as an 8-kb transcript; a 4.5-kb transcript was detected in some tissues and cell lines at variable levels. Highest expression was in brain, heart, prostate, ovary, small intestine, and colon, with moderate or low expression in other tissues. By in situ hybridization, Call was found to be expressed regionally in a timely fashion in the central nervous system, spinal cord, and peripheral nervous system during rat development.
By immunohistochemical analysis of cultured mouse hippocampal neurons, Leshchyns'ka et al. (2006) found that Chl1 was expressed with L1 on thin axonal neurites, with high expression in presynaptic terminals.
Using mass spectrometry and adult mouse brain proteins immobilized on nitrocellulose, Leshchyns'ka et al. (2006) found that the intracellular domain of Chl1 bound Hsc70 (HSPA8; 600816), an ATPase that uncoats clathrin (see 118955)-coated synaptic vesicles. Mutation analysis revealed that an HPD motif conserved in mouse and human CHL1 was required for the interaction. ADP potentiated interaction between Chl1 and Hsc70. Chl1 accumulated in the presynaptic plasma membrane and recruited Hsc70 in an ADP-dependent manner. In response to synapse activation, Chl1 was targeted to synaptic vesicles by endocytosis. Chl1 deficiency in Chl1 -/- neurons or disruption of the Chl1-Hsc70 interaction by the isolated HPD peptide caused reduced levels of Hsc70 on synaptic vesicles, reduced clathrin release from clathrin-coated synaptic vesicles, and reduced marker dye uptake and release in synaptic boutons.
By FISH, Wei et al. (1998) mapped the CHL1 gene to chromosome 3p26.1.
In a boy with 3p- syndrome (613792), Angeloni et al. (1999) found that the break was distal to the von Hippel-Lindau syndrome gene (VHL; 608537), removing marker D3S18 and the CALL gene. The authors suggested that deletion of 1 copy of the CALL gene may be responsible for mental defects in patients with 3p- syndrome.
In a man with nonspecific mental retardation and a 46,Y, t(X;3)(p22.1;p26.3) translocation, Frints et al. (2003) determined that the translocation breakpoint was in intron 5 of CHL1.
Kozma et al. (2004) studied a family segregating a balanced t(1;3)(q42.3;p25) translocation that led to 2 types of viable unbalanced complements: derivative chromosome 3, resulting in partial trisomy of 1q and partial monosomy of 3p, and derivative chromosome 1, resulting in partial monosomy for 1q and partial trisomy for 3p. The authors noted that both rearrangements led to profound mental and physical retardation and congenital heart defects, but each had a distinct facial dysmorphism. Individuals with the derivative chromosome 3 had a long face, wide eyebrows, small palpebral fissures, hypertelorism, prominent glabella, a large tip of the nose, long philtrum with thin upper lip, and low-set ears.
Frints et al. (2003) determined that mouse Chl1 is highly expressed in the central and peripheral nervous systems. Chl1 expression levels in the hippocampus of Chl1 +/- mice were half of those obtained in wildtype littermates, reflecting a gene dosage effect. Timm staining and synaptophysin immunohistochemistry of the hippocampus showed focal groups of ectopic mossy fiber synapses in the lateral CA3 region, outside the trajectory of the infrapyramidal mossy fiber bundle in Chl1 -/- and Chl1 +/- mice. Behavioral assessment demonstrated mild alterations in the Chl1 -/- animals. Frints et al. (2003) hypothesized that a 50% reduction of CALL expression in the developing brain results in cognitive deficits.
Angeloni, D., Lindor, N. M., Pack, S., Latif, F., Wei, M.-H., Lerman, M. I. CALL gene is haploinsufficient in a 3p- syndrome patient. Am. J. Med. Genet. 86: 482-485, 1999. [PubMed: 10508992] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19991029)86:5<482::aid-ajmg15>3.0.co;2-l]
Frints, S. G. M., Marynen, P., Hartmann, D., Fryns, J.-P., Steyaert, J., Schachner, M., Rolf, B., Craessaerts, K., Snellinx, A., Hollanders, K., D'Hooge, R., De Deyn, P. P., Froyen, G. CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior. Hum. Molec. Genet. 12: 1463-1474, 2003. [PubMed: 12812975] [Full Text: https://doi.org/10.1093/hmg/ddg165]
Kozma, C., Slavotinek, A. M., Meck, J. M. Segregation of a t(1;3) translocation in multiple affected family members with both types of adjacent-1 segregants. Am. J. Med. Genet. 124A: 118-128, 2004. [PubMed: 14699608] [Full Text: https://doi.org/10.1002/ajmg.a.20332]
Leshchyns'ka, I., Sytnyk, V., Richter, M., Andreyeva, A., Puchkov, D., Schachner, M. The adhesion molecular CHL1 regulates uncoating of clathrin-coated synaptic vesicles. Neuron 52: 1011-1025, 2006. [PubMed: 17178404] [Full Text: https://doi.org/10.1016/j.neuron.2006.10.020]
Wei, M.-H., Karavanova, I., Ivanov, S. V., Popescu, N. C., Keck, C. L., Pack, S., Eisen, J. A., Lerman, M. I. In silico-initiated cloning and molecular characterization of a novel human member of the L1 gene family of neural cell adhesion molecules. Hum. Genet. 103: 355-364, 1998. [PubMed: 9799093] [Full Text: https://doi.org/10.1007/s004390050829]