Alternative titles; symbols
HGNC Approved Gene Symbol: CLEC16A
Cytogenetic location: 16p13.13 Genomic coordinates (GRCh38): 16:10,944,564-11,182,186 (from NCBI)
The CLEC16A gene encodes a protein that functions as an E3-ubiquitin ligase involved in the regulation of autophagy and mitophagy (summary by Smits et al., 2023).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) obtained a partial cDNA encoding CLEC16A, which they designated KIAA0350. RT-PCR detected CLEC16A expression in all tissues examined, with highest levels in kidney, testis, and ovary. Nakajima et al. (2002, 2002) extended the partial KIAA0350 sequence and found that the deduced full-length protein contains 1,062 amino acids.
The CLEC16A gene is expressed in all regions of the human brain during all stages of human development, including during the embryonic stages and adulthood, compatible with a role in brain development (summary by Smits et al., 2023). In HEK293 cells, Smits et al. (2023) found that CLEC16A localized to early endosomes and interacted strongly with TRIM27 (602165).
By radiation hybrid analysis, Nagase et al. (1997) mapped the CLEC16A gene to chromosome 16.
Hakonarson et al. (2007) noted that the CLEC16A gene maps to chromosome 16p13.
Association with Type I Diabetes Mellitus
The Wellcome Trust Case Control Consortium (2007) reported an association between rs12708716 in the KIAA0350 gene and type 1 diabetes (222100) (p = 1.28 x 10(-8); OR, 0.77). In a study of 4,000 individuals with type 1 diabetes, 5,000 controls, and 2,997 family trios independent of the Wellcome Trust Case Control Consortium (2007) study, Todd et al. (2007) confirmed the previously reported association of rs12708716 (p = 20.8 x 10(-13); combined with WTCCC p = 2.57 x 10(-18)).
To identify genetic factors that increase the risk of type 1 diabetes, Hakonarson et al. (2007) performed a genomewide association study in a large pediatric cohort of European descent. In addition to confirming previously identified loci, they found that type 1 diabetes was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13 that contains the KIAA0350 gene, which is predicted to encode a sugar-binding, C-type lectin. Three common noncoding variants of this gene (rs2903692, rs725613, and rs17673553) in strong linkage disequilibrium reached genomewide significance for association with type 1 diabetes. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. The combined P values for these SNPs ranged from 2.74 x 10(-5) to 6.7 x 10(-7).
Associations with Other Disorders
For discussion of a possible association between variation in the CLEC16A gene and susceptibility to multiple sclerosis, see MS (126200).
For discussion of a possible association between variation in the CLEC16A gene and selective immunoglobulin A deficiency, see IGAD1 (137100).
In a 22-week-old fetus (family 1) and a 6-year-old girl (family 2), both born of consanguineous parents, with a severe neurodevelopmental disorder with growth retardation, Smits et al. (2023) identified homozygous putative loss-of-function variants in the CLEC16A gene: a splice site variant (c.2062+5G-A), resulting the skipping of exon 19, and a frameshift variant (c.-4_12del), predicted to disrupt the initiation codon. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were either not present in the gnomAD database or found at a low frequency in the heterozygous state. The unaffected parents in family 1 carried the variant in the heterozygous state, confirming segregation. Segregation studies were not available for family 2. Family 1 contained 2 additional affected patients, a boy who died at 5 months of age and a fetus terminated at 17 weeks' gestation; DNA was not available from these individuals. All 4 of these patients had growth failure with short stature and microcephaly. The 2 patients who survived birth showed profound global developmental delay with hypotonia, poor head control, lack of speech, and poor or absent eye contact. Additional variable features included seizures, hearing loss, and tetraplegia. Brain atrophy, ventriculomegaly, and hypoplasia or agenesis of the corpus callosum were found on brain imaging. In vitro silencing of the CLEC16A gene in HEK293 cells resulted in the accumulation of TRIM27 (602165) and an increase in F-actin in early endosomes. The authors noted that these abnormalities can impair proper endosomal trafficking and disrupt the retromer retrograde vesicular complex. Expression of the C-terminally deleted splice variant (Asn688ArgfsTer80) in HEK293 cells disrupted the interaction of CLEC16A and TRIM27. The splice site variant was also unable to rescue lysosomal, autophagosomal, and mitosomal defects in clec16a-null zebrafish, suggesting that it results in a loss-of-function effect (see ANIMAL MODEL).
Smits et al. (2023) found that CRISPR/Cas9-mediated knockdown of the clec16a gene in zebrafish resulted in an increase of lysosomes and autophagosomes in the developing brain compared to controls, suggesting abnormal autophagocytosis. The abnormal accumulation of these acidic compartments was observed in radial glial cells, neuronal stem cells, and microglia. An abnormal accumulation of unhealthy damaged mitochondria was also observed, suggesting dysregulated mitophagy.
Hakonarson, H., Grant, S. F. A., Bradfield, J. P., Marchand, L., Kim, C. E., Glessner, J. T., Grabs, R., Casalunovo, T., Taback, S. P., Frackelton, E. C., Lawson, M. L., Robinson, L. J., and 11 others. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448: 591-594, 2007. [PubMed: 17632545] [Full Text: https://doi.org/10.1038/nature06010]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Nakajima, D., Okazaki, N., Yamakawa, H., Kikuno, R., Ohara, O., Nagase, T. Construction of expression-ready cDNA clones for KIAA genes: manual creation of 330 cDNA clones (Supplement). DNA Res. 9: 107-115, 2002. [PubMed: 12168950] [Full Text: https://doi.org/10.1093/dnares/9.3.107]
Nakajima, D., Okazaki, N., Yamakawa, H., Kikuno, R., Ohara, O., Nagase, T. Construction of expression-ready cDNA clones for KIAA genes: manual creation of 330 cDNA clones. DNA Res. 9: 99-106, 2002. [PubMed: 12168954] [Full Text: https://doi.org/10.1093/dnares/9.3.99]
Smits, D. J., Dekker, J., Schot, R., Tabarki, B., Alhashem, A., Demmers, J. A. A., Dekkers, D. H. W., Romito, A., van der Spek, P. J., van Ham, T. J., Bertoli-Avella, A. M., Mancini, G. M. S. CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment. Hum. Genet. 142: 379-397, 2023. [PubMed: 36538041] [Full Text: https://doi.org/10.1007/s00439-022-02511-3]
Todd, J. A., Walker, N. M., Cooper, J. D., Smyth, D. J., Downes, K., Plagnol, V., Bailey, R., Nejentsev, S., Field, S. F., Payne, F., Lowe, C. E., Szeszko, J. S., and 30 others. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39: 857-864, 2007. [PubMed: 17554260] [Full Text: https://doi.org/10.1038/ng2068]
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678, 2007. [PubMed: 17554300] [Full Text: https://doi.org/10.1038/nature05911]