Alternative titles; symbols
HGNC Approved Gene Symbol: KANSL1
SNOMEDCT: 717338006;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38) : 17:46,029,916-46,225,367 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Koolen-De Vries syndrome | 610443 | Autosomal dominant | 3 |
The KANSL1 gene encodes a nuclear protein that plays a role in chromatin modification. It is a member of a histone acetyltransferase (HAT) complex (Smith et al., 2005).
By sequencing clones obtained from a size-fractionated adult human brain cDNA library, Nagase et al. (1999) cloned KIAA1267. The deduced protein contains 1,105 amino acids. RT-PCR ELISA detected high expression in liver and intermediate expression in all other adult and fetal tissues and specific adult brain regions examined, except subthalamic nuclei, where no expression was detected.
Smith et al. (2005) noted that KIAA1267, which they called MSL1V1, and MSL1 (614801) share similarity at their C termini.
Smith et al. (2005) showed that MSL1V1 associated with MOF (MYST1; 609912) in a protein complex that showed histone acetyltransferase (HAT) activity toward nucleosomal histone H4 (see 602822). This MOF complex showed a strong preference for acetylation of H4 lys16 (H4K16).
By radiation hybrid analysis, Nagase et al. (1999) mapped the KIAA1267 gene to chromosome 17.
In a girl with mental retardation and characteristic facial features (Koolen-de Vries syndrome; KDVS; 610443), Zollino et al. (2012) identified a de novo heterozygous truncating mutation in the KANSL1 gene (612452.0001). The girl had classic features of chromosome 17q21.31 deletion syndrome, but did not have a deletion on FISH or array CGH analysis; the mutation was identified by exome sequencing. Direct sequencing of this gene in another unrelated girl with features of the disorder in whom no deletion could be detected identified a second de novo truncating mutation (612452.0002). Both had failure to thrive in infancy, hypotonia, delayed psychomotor development, and a friendly demeanor. Characteristic facial features included broad forehead, upslanting palpebral fissures, epicanthal folds, 'pear'-shaped nose with bulbous nasal tip, long philtrum, large ears, broad chin, abnormal hair texture, and sparse eyebrows. Both also had joint hyperextensibility. The findings indicated that point mutation in the KANSL1 gene is sufficient for full manifestations of chromosome 17q21.31 deletion syndrome, and indicated that it is a monogenic disorder caused by haploinsufficiency of KANSL1.
By Sanger sequencing of the KANSL1 gene in 16 individuals with features of 17q21.31 deletion syndrome who did not have copy number variations in the MAPT (157140) or KANSL1 genes, Koolen et al. (2012) identified different de novo heterozygous truncating mutations in the KANSL1 gene (612452.0003 and 612452.0004) in 2 unrelated patients. Both patients had delayed psychomotor development, intellectual disability, hypotonia, friendly personality, and characteristic facial features, including broad forehead, long face, upslanting palpebral fissures, epicanthal folds, and tubular nose with bulbous nasal tip. Both also had joint laxity, slender lower limbs, pes planus, sacral dimple, and abnormal hair color or texture. One patient had additional features, including cleft lip/palate, ventricular septal defect, cryptorchidism, hypermetropia, strabismus, and scoliosis. Whole-transcriptome sequencing of 3 individuals with the classic 17q21.31 deletion showed that expression levels of KANSL1 were reduced by half. Whole-transcriptome sequencing of 1 of the patients with a point mutation showed differential expression of similar genes as those in patients with deletions; these genes are believed to be involved in neuronal/synaptic processes. The findings showed that haploinsufficiency of KANSL1 is sufficient to cause the classic 17q21.31 microdeletion syndrome phenotype, and provided evidence that the histone acetyltransferase complex may have a role in human cognitive function and developmental processes.
Koolen et al. (2016) reported 45 patients with KDVS confirmed by genetic analysis, including 33 with a 17q21.21 microdeletion encompassing the KANSL1 gene and 12 with a de novo heterozygous mutation in KANSL1 (see, e.g., 612452.0004-612452.0006), all of which were predicted to result in haploinsufficiency. Functional studies of the variants were not performed. Koolen et al. (2016) noted that genetic testing of the 17q21.31 locus can be challenging because of the structural complexity of the genomic region. There were no differences of clinical importance between the 2 groups, indicating that haploinsufficiency for KANSL1 is sufficient to cause the core phenotype.
Lone et al. (2010) identified the Drosophila Waharan gene (Wah), a nuclear protein that is a potential homolog of KANSL1, as a regulator of endosomal trafficking. Knockdown of Wah in Drosophila caused novel accumulations of tightly packed electron-dense tubules in muscle. These tubules coincided with sites at which ubiquitylated proteins and endosomal and lysosomal markers coaccumulated. The findings suggested a relationship between nuclear functions and endolysosomal trafficking.
Koolen et al. (2012) demonstrated that tissue-specific knockdown of Wah in the mushroom bodies of the Drosophila brain caused a 25% reduction in learning ability, confirming an important role for this gene in the regulation of complex brain function.
In a 3-year-old Italian girl with Koolen-de Vries syndrome (KDVS; 610443), Zollino et al. (2012) identified a de novo heterozygous 1816C-T transition in exon 6 of the KANSL1 gene, resulting in an arg606-to-ter (R606X) substitution. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. The mutation was not found in multiple SNP databases or in 400 Italian controls.
In a 14-year-old Italian girl with Koolen-de Vries syndrome (KDVS; 610443), Zollino et al. (2012) identified a de novo heterozygous 2-bp deletion (2785_2787delAG) in exon 13 of the KANSL1 gene, resulting in a frameshift and premature termination (Arg929GlyfsTer44). The mutation was not found in multiple SNP databases or in 400 Italian controls.
In a 3-year-old Caucasian girl with Koolen-de Vries syndrome (KDVS; 610443), Koolen et al. (2012) identified a de novo heterozygous 916C-T transition in exon 3 of the KANSL1 gene, resulting in a gln306-to-ter (Q306X) substitution.
Koolen et al. (2016) stated that the c.916C-T transition (c.916C-T, NM_001193466.1) in the KANSL1 gene occurs in exon 2.
In a 13-year-old boy with Koolen-de Vries syndrome (KDVS; 610443), Koolen et al. (2012) identified a de novo heterozygous G-to-A transition in intron 6 of the KANSL1 gene (1652+1G-A), resulting in the skipping of exon 6, a frameshift, and premature termination. The patient also had joint laxity, cleft lip and palate, hypermetropia, strabismus, ventricular septal defect, cryptorchidism, and scoliosis.
Koolen et al. (2016) identified a de novo heterozygous c.1652+1G-A mutation in the KANSL1 gene in a second patient (patient 35) with KDVS.
In a 5-year-old boy (patient 36) with Koolen-de Vries syndrome (KDVS; 610443), Koolen et al. (2016) identified a de novo heterozygous 2-bp deletion (c.985_986del, NM_001193466.1) in exon 2 of the KANLS1 gene, predicted to result in a frameshift and premature termination (Leu329GlufsTer22).
In a 10-year-old girl (patient 41) with Koolen-de Vries syndrome (KDVS; 610443), Koolen et al. (2016) identified a de novo heterozygous 1-bp deletion (c.572del, NM_001193466.1) in exon 2 of the KANLS1 gene, predicted to result in a frameshift and premature termination (Gly191ValfsTer11).
Koolen, D. A., Kramer, J. M., Neveling, K., Nillesen, W. M., Moore-Barton, H. L., Elmslie, F. V., Toutain, A., Amiel, J., Malan, V., Tsai, A. C.-H., Cheung, S. W., Gilissen, C., and 13 others. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nature Genet. 44: 639-641, 2012. [PubMed: 22544363] [Full Text: https://doi.org/10.1038/ng.2262]
Koolen, D. A., Pfundt, R., Linda, K., Beunders, G., Veenstra-Knol, H. E., Conta, J. H., Fortuna, A. M., Gillessen-Kaesbach, G., Dugan, S., Halbach, S., Abdul-Rahman, O. A., Winesett, H. M., and 38 others. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant. Europ. J. Hum. Genet. 24: 652-659, 2016. [PubMed: 26306646] [Full Text: https://doi.org/10.1038/ejhg.2015.178]
Lone, M., Kungl, T., Koper, A., Bottenberg, W., Kammerer, R., Klein, M., Sweeney, S. T., Auburn, R. P., O'Kane, C. J., Prokop, A. The nuclear protein Waharan is required for endosomal-lysosomal trafficking in Drosophila. J. Cell Sci. 123: 2369-2374, 2010. [PubMed: 20551180] [Full Text: https://doi.org/10.1242/jcs.060582]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Smith, E. R., Cayrou, C., Huang, R., Lane, W. S., Cote, J., Lucchesi, J. C. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Molec. Cell. Biol. 25: 9175-9188, 2005. Note: Erratum: Molec. Cell. Biol. 26: 387 only, 2006. [PubMed: 16227571] [Full Text: https://doi.org/10.1128/MCB.25.21.9175-9188.2005]
Zollino, M., Orteschi, D., Murdolo, M., Lattante, S., Battaglia, D., Stefanini, C., Mercuri, E., Chiurazzi, P., Neri, G., Marangi, G. Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nature Genet. 44: 636-638, 2012. [PubMed: 22544367] [Full Text: https://doi.org/10.1038/ng.2257]