Alternative titles; symbols
HGNC Approved Gene Symbol: CHIT1
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:203,216,079-203,230,099 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | [Chitotriosidase deficiency] | 614122 | Autosomal recessive | 3 |
The CHIT1 gene encodes plasma methylumbelliferyl tetra-N-acetylchitotetraoside hydrolase (chitotriosidase), a human chitinase (EC 3.2.1.14). Chitinases play a role in degrading the chitin walls of some microorganisms (Boot et al., 1995).
Renkema et al. (1995) purified and characterized the chitotriosidase protein from the spleen of a patient with Gaucher disease (230800) who had increased serum CHIT1 enzyme activity. Two major isoforms with isoelectric points of 7.2 and 8.0 and molecular masses of 50 and 39 kD, respectively, were found to have identical N-terminal amino acid sequences. An antiserum raised against the purified 39-kD chitotriosidase precipitated all isozymes. The findings suggested that a single gene encodes the different isoforms of chitotriosidase. The authors postulated that the enzyme may be involved in defense against and in degradation of chitin-containing pathogens such as fungi, nematodes, and insects.
Boot et al. (1995) isolated a cDNA corresponding to the chitotriosidase gene from a macrophage cDNA library. The deduced 445-amino acid protein has a molecular mass of 49 kD, similar to the larger isoform detected by Renkema et al. (1995). Secretion of active chitotriosidase was obtained after transient transfection of COS-1 cells with the cloned cDNA. Chitotriosidase contains several regions with high homology to those present in chitinases from different species belonging to family 18 of glycosylhydrolases. Northern blot analysis showed that expression of chitotriosidase mRNA occurred only at a late stage of differentiation of monocytes to activated macrophages in cell culture. The authors speculated that the enzyme may play a role in the degradation of chitin-containing pathogens.
Boot et al. (1998) determined that the CHIT1 gene contains 12 exons and spans about 20 kb.
Eiberg and Den Tandt (1997) mapped the CHIT locus to chromosome 1q31-qter between flanking markers D1S191 and D1S245. By fluorescence in situ hybridization, Boot et al. (1998) assigned the CHIT gene to 1q31-q32.
Hollak et al. (1994) observed a very marked increase (more than 600-fold) of chitotriosidase activity in the plasma of 30 of 32 symptomatic patients with type I Gaucher disease (230800), which is due to mutation in the gene encoding beta-glucosidase (GBA; 606463). The increase in plasma chitotriosidase that they observed in Gaucher disease patients was far more pronounced than the increase in alkaline phosphatase (ALPL; 171760), which had been used as an important diagnostic hallmark of the disease. Chitotriosidase activity declined dramatically during enzyme supplementation therapy. In contrast, 3 GBA-deficient individuals without clinical symptoms had only slight increases in chitotriosidase. The authors considered it unlikely that chitotriosidase itself contributes to the clinical presentation of Gaucher disease. Hollak et al. (1994) noted that the similarity between lysozyme (LYZ; 153450) and chitotriosidase with respect to catalytic activity toward particular substrates suggested that the latter may also function in host defense mechanisms, e.g., through cleavage of bacterial cell wall polysaccharide. Hollak et al. (1994) suggested that the macrophages loaded with glucosylceramide in Gaucher disease are the main source of the plasma enzyme activity. No elevation, or only moderate elevation, of plasma chitotriosidase was found in a variety of granulomatous immunologic disorders.
Boot et al. (1995) noted that homologous chitinases in plants are known to defend against fungal pathogens. The bactericidal function of lysozyme is also well established; nevertheless, in rabbits an inherited deficiency in lysozyme occurs that seems to have little consequence for susceptibility to infections. The diverse array of defense mechanisms of the immune system in mammals probably renders sufficient tolerance to defects in single enzymes such as lysozyme and chitotriosidase.
By comparing the antifungal properties of human macrophage chitotriosidase and its isolated domains, Vandevenne et al. (2011) showed that the catalytic domain was sufficient for antifungal activity and tended to be more efficient than the intact enzyme. In contrast, the chitin-binding domain did not possess any antifungal properties. Mutations in chitotriosidase that rendered the macrophage enzyme inactive could be compensated by lysozyme, which had even greater antifungal activity than chitotriosidase, as well as antibacterial activity.
By comparative analysis of spinal cords of young and aged cynomolgus monkeys, Sun et al. (2023) showed that Chit1-positive microglia preferentially localized around motor neurons (MNs) and were associated with aging of spinal cords. Accumulation of Chit1-positive microglia induced senescence of MNs by activating SMAD signaling (see 601595). Treatment of young monkeys with Chit1 induced MN senescence phenotypes that were similar to those observed in MNs of aged monkeys in vivo. Analysis of human embryonic stem cell-derived MNs showed that CHIT1 secreted by microglia induced senescence through paracrine signaling. In addition, Chit1-driven MN aging and its prosenescence effects on MNs were counteracted by the geroprotective compound ascorbic acid in aged monkeys.
In individuals with chitotriosidase deficiency (CHITD; 614122), Boot et al. (1998) identified a homozygous 24-bp duplication in the CHIT1 gene (600031.0001). The observed carrier frequency of about 35% indicated that the duplication is the predominant cause of chitotriosidase deficiency. The presence of the duplication in individuals from various ethnic backgrounds suggested that this mutation is relatively old.
Grace et al. (2007) noted that the identification of CHIT1 gene mutations that alter plasma activity is important for the use of this biomarker to monitor disease activity and therapeutic response in Gaucher disease. They genotyped the CHIT1 gene in 320 unrelated patients with Gaucher disease, including 272 of Ashkenazi Jewish descent. Among all patients, 4% and 37.2% were homozygous and heterozygous, respectively, for the 24-bp duplication. In addition, Grace et al. (2007) identified 3 novel mutations in the CHIT1 gene (600031.0002-600031.0004) in individuals with Gaucher disease and chitotriosidase deficiency.
Boot et al. (1998) found that chitotriosidase deficiency (CHITD; 614122) can be caused by a 24-bp duplication in exon 10 of the CHIT1 gene, resulting in activation of a cryptic 3-prime splice site, generating an mRNA with an in-frame deletion of 87 nucleotides. All chitotriosidase-deficient individuals tested were homozygous for the duplication. Among 171 Dutch persons, 6.4% were homozygous and 35.1% were heterozygous for the mutation. Among 68 Ashkenazi Jewish subjects, 5.9% were homozygous and 33.8% were heterozygous. The mutant chitotriosidase is predicted to lack amino acids 344-372. On the basis of homology with several chitinases for which the 3-dimensional structure has been resolved by crystallographic analysis, the authors predicted that the internal deletion in the mutant chitotriosidase prevents the formation of a proper barrel conformation, with resulting loss of chitinolytic activity.
Among a total of 320 unrelated patients with Gaucher disease (232800), including 272 of Ashkenazi Jewish descent, Grace et al. (2007) found that 4% and 37.2% were homozygous or heterozygous for the CHIT1 24-bp dup, respectively. The allele frequency was 0.227.
In a Caribbean Hispanic/African type 1 Gaucher disease (230800) patient with chitotriosidase deficiency (CHITD; 614122), Grace et al. (2007) identified a complex allele of the CHIT1 gene with 3 different variations in cis: a 1060G-A transition in exon 10 resulting in a gly354-to-arg (G354R) substitution, a 1155G-A transition in exon 10 resulting in a synonymous leu385-to-leu (L385L) substitution, and a 4-bp deletion in intron 10 (1156delGTAA). The complex allele was designated 'E/I-10' (exon/intron-10) allele. The patient was compound heterozygous for the E/I-10 complex allele and the common 24-bp duplication (600031.0001). In vitro functional expression studies showed that the complex mutant had no residual enzyme activity. Further screening identified the complex allele in individuals of Caribbean Hispanic, Dominican, Caribbean Black, Puerto Rican, and American Black descent. It was not identified in those of Caucasian or Ashkenazi Jewish descent.
In a type I Gaucher disease (230800) patient with chitotriosidase deficiency (CHITD; 614122), Grace et al. (2007) identified a 220G-A transition in exon 3 of the CHIT1 gene, resulting in a glu74-to-lys (E74K) substitution. In vitro functional expression studies showed that the E74K mutant had 51% activity compared to control values. The E74K allele was found in 3 (1.4%) of 208 Ashkenazi Jewish alleles, but not in non-Ashkenazi Jewish alleles, indicating that it is very rare. This mutation was not found in normal controls.
In 3 Ashkenazi Jewish type I Gaucher disease (230800) patients with chitotriosidase deficiency (CHITD; 614122), Grace et al. (2007) identified a 304G-A transition in exon 4 of the CHIT1 gene, resulting in a gly102-to-ser (G102S) substitution. In vitro functional expression studies showed that the G102S mutant had 23% activity compared to control values. The G102S allele had a frequency of 0.2 to 0.3 in various control populations.
Boot, R. G., Renkema, G. H., Strijland, A., van Zonneveld, A. J., Aerts, J. M. F. G. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J. Biol. Chem. 270: 26252-26256, 1995. [PubMed: 7592832] [Full Text: https://doi.org/10.1074/jbc.270.44.26252]
Boot, R. G., Renkema, G. H., Verhoek, M., Strijland, A., Bliek, J., de Meulemeester, T. M. A. M. O., Mannens, M. M. A. M., Aerts, J. M. F. G. The human chitotriosidase gene: nature of inherited enzyme deficiency. J. Biol. Chem. 273: 25680-25685, 1998. [PubMed: 9748235] [Full Text: https://doi.org/10.1074/jbc.273.40.25680]
Eiberg, H., Den Tandt, W. R. Assignment of human plasma methylumbelliferyl-tetra-N-acetylchitotetraoside hydrolase or chitinase to chromosome 1q by a linkage study. Hum. Genet. 101: 205-207, 1997. [PubMed: 9402970] [Full Text: https://doi.org/10.1007/s004390050615]
Grace, M. E., Balwani, M., Nazarenko, I., Prakash-Cheng, A., Desnick, R. J. Type 1 Gaucher disease: null and hypomorphic novel chitotriosidase mutations--implications for diagnosis and therapeutic monitoring. Hum. Mutat. 28: 866-873, 2007. [PubMed: 17464953] [Full Text: https://doi.org/10.1002/humu.20524]
Hollak, C. E. M., van Weely, S., van Oers, M. H. J., Aerts, J. M. F. G. Marked elevation of plasma chitotriosidase activity: a novel hallmark of Gaucher disease. J. Clin. Invest. 93: 1288-1292, 1994. [PubMed: 8132768] [Full Text: https://doi.org/10.1172/JCI117084]
Renkema, G. H., Boot, R. G., Muijsers, A. O., Donker-Koopman, W. E., Aerts, J. M. F. G. Purification and characterization of human chitotriosidase, a novel member of the chitinase family of proteins. J. Biol. Chem. 270: 2198-2202, 1995. [PubMed: 7836450] [Full Text: https://doi.org/10.1074/jbc.270.5.2198]
Sun, S., Li, J., Wang, S., Li, J., Ren, J., Bao, Z., Sun, L., Ma, X., Zheng, F., Ma, S., Sun, L., Wang, M., and 25 others. CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord. Nature 624: 611-620, 2023. [PubMed: 37907096] [Full Text: https://doi.org/10.1038/s41586-023-06783-1]
Vandevenne, M., Campisi, V., Freichels, A., Gillard, C., Gaspard, G., Frere, J.-M., Galleni, M., Filee, P. Comparative functional analysis of the human macrophage chitotriosidase. Protein Sci. 20: 1451-1463, 2011. [PubMed: 21674664] [Full Text: https://doi.org/10.1002/pro.676]