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Other entities represented in this entry:
HGNC Approved Gene Symbol: KNL1
Cytogenetic location: 15q15.1 Genomic coordinates (GRCh38) : 15:40,594,249-40,664,342 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.1 | Microcephaly 4, primary, autosomal recessive | 604321 | Autosomal recessive | 3 |
The CASC5 gene encodes a protein that localizes to the kinetochore and performs 2 functions during mitosis: it is required for correct attachment of centromeres to the microtubule apparatus and is essential for spindle-assembly checkpoint signaling (summary by Genin et al., 2012).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned KIAA1570. RT-PCR detected highest expression in adult testis, adult kidney, and fetal liver. Lower expression was detected in adult ovary and fetal brain, and little to no expression was detected in all other adult tissues and specific brain regions examined.
By screening a HeLa cell cDNA library with a probe derived from an ALL1 (159555) fusion partner, followed by screening a testis cDNA library and 5-prime and 3-prime RACE, Hayette et al. (2000) cloned AF15q14. The deduced 1,833-amino acid protein has a calculated molecular mass of 206 kD. AF15q14 contains a C-terminal bipartite nuclear localization signal. Northern blot analysis of HeLa cells detected a transcript of about 8.5 kb. RNA dot blot analysis of adult tissues found AF15q14 expression restricted to thymus, testis, and bone marrow. Expression was ubiquitous in fetal tissues.
Using the transcription factor GCF (TCF9; 189901) as bait in a yeast 2-hybrid screen of a human B-cell line, followed by RACE, Takimoto et al. (2002) cloned D40. Northern blot analysis of several human tissues detected a major 8.5-kb transcript and a minor 7.0-kb transcript. Expression was highest in testis, lower in placenta, and very low or undetectable in all other tissues tested. Takimoto et al. (2002) found D40 expression in several primary tumors and tumor cell lines. Expression did not correlate with either histologic type or pathologic tumor stage. However, D40 expression was observed more frequently in poorly differentiated tumors than in well or moderately differentiated ones, and D40 expression was higher in primary lung tumors from patients who smoked than in those from nonsmokers.
By screening testis and thymus cDNA libraries and by 5-prime RACE, Kuefer et al. (2003) cloned AF15q14. The deduced 2,342-amino acid protein has a calculated molecular mass of 265.3 kD. Northern blot analysis detected AF15q14 transcripts of about 9.5 and 7.5 kb that were abundantly expressed in testis and thymus, with low levels in placenta. Abundant expression was also detected in fetal liver.
By immunoprecipitation, Obuse et al. (2004) identified 9 proteins, including KIAA1570, that interacted with MIS12 (609178) following overexpression of MIS12 in HeLa cells. The deduced 2,342-amino acid KIAA1570 protein has both N- and C-terminal coiled-coil domains.
By reciprocal immunoprecipitation of transfected proteins from HeLa cells, Obuse et al. (2004) showed that KIAA1570 is part of a centromere complex that includes C20ORF172 (609175), DC8 (609174), MIS12, PMF1 (609176), and HP1-gamma (CBX3; 604477).
Kuefer et al. (2003) determined that the AF15q14 gene contains at least 27 exons and spans at least 68.3 kb. The first exon is noncoding.
By FISH, Wei et al. (1999) mapped the D40 gene to chromosome 15q14-q15. By sequence analysis, Hayette et al. (2000) mapped the AF15q14 gene to chromosome 15q14.
Hayette et al. (2000) described a 48-year-old man with AML-M4 (see 601626) who was cytogenetically characterized as 46,XY,-3,t(11;15)(q23;q14),+mar. The bone marrow was hypercellular, with 80% blast cells. The patient was treated by intensive chemotherapy and died 4 month after diagnosis. The translocation resulted in a in-frame fusion between exon 8 of the MLL gene and exon 10 of the AF15q14 gene. The fusion transcript was predicted to encode a 1,503-amino acid protein composed of 1,418 N-terminal amino acids of MLL and 85 C-terminal amino acids of AF15q14, including the bipartite nuclear localization signal.
Kuefer et al. (2003) identified a similar t(11;15)(q23;q14) in a 3-year-old boy with de novo T-cell acute lymphoblastic leukemia. In this translocation, exon 9 of the MLL gene was fused in-frame to exon 12 of the AF15q14 gene. The deduced 1,886-amino acid fusion protein, which contains the N terminus of MLL up to lys1362 fused to the entire C terminus of AF15q14 starting from residue ile1819, has a calculated molecular mass of 208 kD. It differs from the fusion protein described by Hayette et al. (2000) in that it has a coiled-coil domain but no nuclear localization signal.
In an 11-year-old boy with acute myoblastic leukemia (AML-M2) and a translocation t(11;15)(q23;q14), Chinwalla et al. (2003) identified MLL-AF15q14 and MLL-MPFYVE (619635) fusion transcripts. Both fusion transcripts were in-frame and had the potential to encode novel fusion proteins.
In affected members of 3 consanguineous Moroccan families with autosomal recessive primary microcephaly-4 (MCPH4; 604321), including the family originally reported by Jamieson et al. (1999), Genin et al. (2012) identified a homozygous mutation in the CASC5 gene (M2041I; 609173.0001).
In affected members of a consanguineous Algerian family with primary microcephaly, Saadi et al. (2016) identified homozygosity for the same M2041I mutation in the CASC5 gene that had been identified by Genin et al. (2012) in Moroccan families. Haplotype analysis supported the existence of a common ancestor.
In an African American male infant with primary microcephaly, Zarate et al. (2016) identified compound heterozygosity for a de novo frameshift (609173.0002) mutation and a maternally inherited missense mutation (D2187G; 609173.0003) in the CASC5 gene. (In the article, Zarate et al. (2016) incorrectly stated the protein change as D2178G.) The frameshift mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases; the missense mutation was present in the ExAC database at a low frequency in the general population, but primarily in patients of African ancestry, with a heterozygous minor allele frequency of 0.0034 in that population.
In affected members of 3 consanguineous Moroccan families with autosomal recessive primary microcephaly-4 (MCPH4; 604321), including the family originally reported by Jamieson et al. (1999), Genin et al. (2012) identified a homozygous 6125G-A transition in exon 18 of the CASC5 gene, resulting in a met2041-to-ile (M2041I) substitution at a highly conserved residue. The mutation was not found in 316 control chromosomes or among 9,500 control exomes. The mutation was predicted to inactivate an exonic splicing enhancer, and was demonstrated to result in abnormal splicing and production of a transcript lacking exon 18 and causing premature termination. However, normal CASC5 protein levels were also found in patient lymphoblastoid cells. Patient lymphoblasts showed no abnormalities in mitosis, no changes in growth rate, and no micronuclei. Immunofluorescence studies showed no defects of CASC5 expression in patient fibroblasts, and mitotic spindles were normal. None of the patients developed leukemia, consistent with normal CASC5 function in nonneurologic cells. Although this mutant CASC5 appeared to function normally in patient lymphoblasts and fibroblasts, Genin et al. (2012) speculated that it may express the defect only in neural cells.
In affected members of a consanguineous Algerian family with primary microcephaly, Saadi et al. (2016) identified homozygosity for the M2041I mutation in the CASC5 gene. Haplotype analysis supported the existence of a common ancestor in the Algerian family and the Moroccan families reported by Genin et al. (2012).
In an African American male infant with primary microcephaly (MCPH4; 604321), Zarate et al. (2016) identified compound heterozygosity for 2 mutations in the CASC5 gene: a de novo duplication (c.5262dupT, NM_170589.4), resulting in a frameshift and premature termination (Ile1755TyrfsTer2), and a maternally inherited c.6560A-G transition, resulting in an asp2187-to-gly (D2187G; 609173.0003) substitution. (In the article, Zarate et al. (2016) incorrectly stated the protein change as asp2178-to-gly.) The frameshift mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases; the D2187G mutation was present in the ExAC database at a low frequency in the general population, but primarily in patients of African ancestry, with a heterozygous minor allele frequency of 0.0034 in that population.
For discussion of the c.6560A-G transition (c.6560A-G, NM_170589.4) in the CASC5 gene, resulting in an asp2187-to-gly (D2187G) substitution, that was found in compound heterozygous state in an African American male infant with primary microcephaly (MCPH4; 604321) by Zarate et al. (2016), see 609173.0002. (In the article, Zarate et al. (2016) incorrectly stated the protein change as asp2178-to-gly.)
Chinwalla, V., Chien, A., Odero, M., Neilly, M. B., Zeleznik-Le, N. J., Rowley, J. D. A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15. Oncogene 22: 1400-1410, 2003. [PubMed: 12618766] [Full Text: https://doi.org/10.1038/sj.onc.1206273]
Genin, A., Desir, J., Lambert, N., Biervliet, M., Van Der Aa, N., Pierquin, G., Killian, A., Tosi, M., Urbina, M., Lefort, A., Libert, F., Pirson, I., Abramowicz, M. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum. Molec. Genet. 21: 5306-5317, 2012. [PubMed: 22983954] [Full Text: https://doi.org/10.1093/hmg/dds386]
Hayette, S., Tigaud, I., Vanier, A., Martel, S., Corbo, L., Charrin, C., Beillard, E., Deleage, G., Magaud, J. P., Rimokh, R. AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14). Oncogene 19: 4446-4450, 2000. [PubMed: 10980622] [Full Text: https://doi.org/10.1038/sj.onc.1203789]
Jamieson, C. R., Govaerts, C., Abramowicz, M. J. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. (Letter) Am. J. Hum. Genet. 65: 1465-1469, 1999. [PubMed: 10521316] [Full Text: https://doi.org/10.1086/302640]
Kuefer, M. U., Chinwalla, V., Zeleznik-Le, N. J., Behm, F. G., Naeve, C. W., Rakestraw, K. M., Mukatira, S. T., Raimondi, S. C., Morris, S. W. Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14). Oncogene 22: 1418-1424, 2003. [PubMed: 12618768] [Full Text: https://doi.org/10.1038/sj.onc.1206272]
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Obuse, C., Iwasaki, O., Kiyomitsu, T., Goshima, G., Toyoda, Y., Yanagida, M. A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1. Nature Cell Biol. 6: 1135-1141, 2004. [PubMed: 15502821] [Full Text: https://doi.org/10.1038/ncb1187]
Saadi, A., Verny, F., Siquier-Pernet, K., Bole-Feysot, C., Nitschke, P., Munnich, A., Abada-Dendib, M., Chaouch, M., Abramowicz, M., Colleaux, L. Refining the phenotype associated with CASC5 mutation. Neurogenetics 17: 71-78, 2016. [PubMed: 26626498] [Full Text: https://doi.org/10.1007/s10048-015-0468-7]
Takimoto, M., Wei, G., Dosaka-Akita, H., Mao, P., Kondo, S., Sakuragi, N., Chiba, I., Miura, T., Itoh, N., Sasao, T., Koya, R. C., Tsukamoto, T., Fujimoto, S., Katoh, H., Kuzumaki, N. Frequent expression of new cancer/testis gene D40/AF15q14 in lung cancers of smokers. Brit. J. Cancer 86: 1757-1762, 2002. [PubMed: 12087463] [Full Text: https://doi.org/10.1038/sj.bjc.6600328]
Wei, G., Takimoto, M., Yoshida, I., Mao, P., Koya, R. C., Miura, T., Kuzumaki, N. Chromosomal assignment of a novel human gene D40. Nucleic Acids Symp. Ser. 42: 71-72, 1999. [PubMed: 10780384] [Full Text: https://doi.org/10.1093/nass/42.1.71]
Zarate, Y. A., Kaylor, J. A., Bosanko, K., Lau, S., Vargas, J., Gao, H. First clinical report of an infant with microcephaly and CASC5 mutations. (Letter) Am. J. Med. Genet. 170A: 2215-2218, 2016. [PubMed: 27149178] [Full Text: https://doi.org/10.1002/ajmg.a.37726]