Atlas of Genetics and Cytogenetics in Oncology and Haematology

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KNL1 (cancer susceptibility candidate 5)

Written2000-03Jean-Loup Huret, Christiane Charrin
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH); Service d'Hematologie, Hopital Edouard Herriot, Lyon, France (CC).
Updated2006-09Masato Takimoto
Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
Updated2012-06Masato Takimoto
Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan

(Note : for Links provided by Atlas : click)


Other namesCT29
HGNC (Hugo) KNL1
LocusID (NCBI) 57082
Atlas_Id 318
Location 15q15.1  [Link to chromosome band 15q15]
Location_base_pair Starts at 40886447 and ends at 40954881 bp from pter ( according to hg19-Feb_2009)
Fusion genes
(updated 2016)
KNL1 (15q15.1) / ADAMTS9-AS2 (3p14.1)KNL1 (15q15.1) / KMT2A (11q23.3)KMT2A (11q23.3) / KNL1 (15q15.1)


Note Whole genomic size is not determined, but consists of at least 10 exons.
Transcription D40/CASC5 mRNA expression is dominant in normal human testis and slight expression are observed in other organs, such as placenta. At least two alternative isoforms of cDNA were identified.
Analysis on cancer cell lines, such as HeLa, gave single band with 8,5 kb. There is another alternative splicing site at the 5' side of this gene that generates a short exon with 78 bp in cDNA. There are potential other alternative splicing at cancer cell lines.
Northern blotting analysis on testis shows two bands with size of approximately 6 and 8,5 kb which are probably derived from the two isoforms.


Description Encodes 1833 amino acids and 2342 amino acids.
Expression D40/CASC5 protein expressions with molecular weight of approximately 250 kDa and 300 kDa are observed in human testicular germ cells and cancer cell lines.
Localisation In germ cell of testis, significant high expressions of D40 protein are observed in nucleus of spermatocytes and pre-acrosome of spermatids. As D40 protein has no hydrophobic signal peptide in its amino terminal, it localizes outer surface of pre-acrosome membrane.
Kinetochore proteins, Knl 1 in C. elegans, Spc7 in Schizosaccharomyces pombe, Spc105c in Saccharomyces cerevisiae and dmSpc105 in Drosophila have sequence homology to D40, and it also was shown that D40 is localized in kinetochore in a human cancer cell line.
Function D40 is a one of kinetochore protein, constituting KMN (Knl1/Mis12 complex/Nde80 complex) network. KMN network is the central hub of outer kinetochore, not only connecting mitotic chromosomes and spindles but also coordinating microtubule-binding and spindle assembly checkpoint (SAC) signaling. There are two microtubule binding activity in KMN network, one in Ndc80/Nurf and the other in D40/Knl1 The N-terminal region of D40 protein binds to protein phosphatase I (PP1) and SAC proteins, Bub1 and BubR1, while the C-terminal half mediates KMN network. D40 binds to Bub1 and BubR1 kinases, through tetratricopeptide repeats (TPRs) of the SAC protein and KI motif of D40. PP1 interacts with RVSF motif of D40 protein, being recruited to kinetochore. PP1 stabilizes microtubule attachments to kinetochores, opposing Aurora B kinase that inactivates microtubule-binding. It is suggested that D40 play a role in SAC silencing through PP1 binding.
The C-terminal region of D40 interacts with Zwint-1 and Mis14 protein. The former mediates the binding D40 to Ndc80 comlpex, and the latter is a part of Mis12 complex.

Implicated in

Entity t(11;15)(q23;q14)/acute non lymphocytic leukemia (AML) -->MLL-CASC5
Note MLL gene and D40 (AF15q14) gene are reported to be translocated each other in three cases of leukemias.
Entity Lung cancer
Note In primary lung cancer, clinicopathological findings correlates with D40 expression. D40 mRNA expression is more frequent in the tumors with low differentiation than the ones with moderate and high differentiation. Further, the tumors derived from smoker express higher incidence of D40 mRNA than the ones from non-smoker. D40 is a member of cancer/testis gene family.
Entity Spermatogenesis
Note D40 expressions in testes of the patients with infertility were significantly lower than normal ones. As D40 protein expressions were observed in spermatocytes in seminiferous tube of human testes, D40 may also play a role in cell division as a kinetochore protein in meiotic cells. As D40 protein expressions are also observed in pre-acrosome of spermatids, especially from its early stage, it might be playing some role in acrosome formation.


The conserved KMN network constitutes the core microtubule-binding site of the kinetochore.
Cheeseman IM, Chappie JS, Wilson-Kubalek EM, Desai A.
Cell. 2006 Dec 1;127(5):983-97.
PMID 17129783
A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15.
Chinwalla V, Chien A, Odero M, Neilly MB, Zeleznik-Le NJ, Rowley JD.
Oncogene. 2003 Mar 6;22(9):1400-10.
PMID 12618766
Microtubule binding by KNL-1 contributes to spindle checkpoint silencing at the kinetochore.
Espeut J, Cheerambathur DK, Krenning L, Oegema K, Desai A.
J Cell Biol. 2012 Feb 20;196(4):469-82. Epub 2012 Feb 13.
PMID 22331849
AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14).
Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Deleage G, Magaud JP, Rimokh R.
Oncogene. 2000 Sep 7;19(38):4446-50.
PMID 10980622
The fission yeast kinetochore component Spc7 associates with the EB1 family member Mal3 and is required for kinetochore-spindle association.
Kerres A, Vietmeier-Decker C, Ortiz J, Karig I, Beuter C, Hegemann J, Lechner J, Fleig U.
Mol Biol Cell. 2004 Dec;15(12):5255-67. Epub 2004 Sep 15.
PMID 15371542
Protein interaction domain mapping of human kinetochore protein Blinkin reveals a consensus motif for binding of spindle assembly checkpoint proteins Bub1 and BubR1.
Kiyomitsu T, Murakami H, Yanagida M.
Mol Cell Biol. 2011 Mar;31(5):998-1011. Epub 2011 Jan 3.
PMID 21199919
Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction.
Krenn V, Wehenkel A, Li X, Santaguida S, Musacchio A.
J Cell Biol. 2012 Feb 20;196(4):451-67. Epub 2012 Feb 13.
PMID 22331848
Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14).
Kuefer MU, Chinwalla V, Zeleznik-Le NJ, Behm FG, Naeve CW, Rakestraw KM, Mukatira ST, Raimondi SC, Morris SW.
Oncogene. 2003 Mar 6;22(9):1418-24.
PMID 12618768
Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase.
Liu D, Vleugel M, Backer CB, Hori T, Fukagawa T, Cheeseman IM, Lampson MA.
J Cell Biol. 2010 Mar 22;188(6):809-20. Epub 2010 Mar 15.
PMID 20231380
A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1.
Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M.
Nat Cell Biol. 2004 Nov;6(11):1135-41. Epub 2004 Oct 24.
PMID 15502821
Molecular analysis of core kinetochore composition and assembly in Drosophila melanogaster.
Przewloka MR, Zhang W, Costa P, Archambault V, D'Avino PP, Lilley KS, Laue ED, McAinsh AD, Glover DM.
PLoS One. 2007 May 30;2(5):e478.
PMID 17534428
The protein encoded by cancer/testis gene D40/AF15q14 is localized in spermatocytes, acrosomes of spermatids and ejaculated spermatozoa.
Sasao T, Itoh N, Takano H, Watanabe S, Wei G, Tsukamoto T, Kuzumaki N, Takimoto M.
Reproduction. 2004 Dec;128(6):709-16.
PMID 15579588
Testis cancer gene D40 expression and its relationship with clinicopathological features in infertile men.
Sasao T, Takimoto M, Itoh N, Maeda T, Tanaka T, Masumori N, Tsukamoto T.
Int J Urol. 2011 Feb;18(2):175-9. doi: 10.1111/j.1442-2042.2010.02692.x. Epub 2011 Jan 12.
PMID 21272090
Cancer/testis antigens, gametogenesis and cancer.
Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ.
Nat Rev Cancer. 2005 Aug;5(8):615-25. (REVIEW)
PMID 16034368
Frequent expression of new cancer/testis gene D40/AF15q14 in lung cancers of smokers.
Takimoto M, Wei G, Dosaka-Akita H, Mao P, Kondo S, Sakuragi N, Chiba I, Miura T, Itoh N, Sasao T, Koya RC, Tsukamoto T, Fujimoto S, Katoh H, Kuzumaki N.
Br J Cancer. 2002 Jun 5;86(11):1757-62.
PMID 12087463
Chromosomal assignment of a novel human gene D40.
Wei G, Takimoto M, Yoshida I, Mao PZ, Koya RC, Miura T, Kuzumaki N.
Nucleic Acids Symp Ser. 1999;(42):71-2.
PMID 10780384
Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface.
Welburn JP, Vleugel M, Liu D, Yates JR 3rd, Lampson MA, Fukagawa T, Cheeseman IM.
Mol Cell. 2010 May 14;38(3):383-92.
PMID 20471944


This paper should be referenced as such :
Takimoto, M
CASC5 (cancer susceptibility candidate 5)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(1):1-2.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Huret, JL ; Charrin, C. AF15q14 (ALL1 fused gene from 15q14). Atlas Genet Cytogenet Oncol Haematol. 2000;4(2):50-50.
Takimoto, M. CASC5 (cancer sensitibity candidate 5). Atlas Genet Cytogenet Oncol Haematol. 2007;11(1):8-9.

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
  t(11;15)(q23;q14) KMT2A/CASC5
11q23 rearrangements (KMT2A) in leukaemia
t(11;15)(q23;q14) KMT2A/CASC5

External links

HGNC (Hugo)KNL1   24054
Entrez_Gene (NCBI)KNL1  57082  kinetochore scaffold 1
AliasesAF15Q14; CASC5; CT29; D40; 
MCPH4; PPP1R55; Spc7; hKNL-1; hSpc105
GeneCards (Weizmann)KNL1
Ensembl hg19 (Hinxton)ENSG00000137812 [Gene_View]  chr15:40886447-40954881 [Contig_View]  KNL1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000137812 [Gene_View]  chr15:40886447-40954881 [Contig_View]  KNL1 [Vega]
ICGC DataPortalENSG00000137812
TCGA cBioPortalKNL1
AceView (NCBI)KNL1
Genatlas (Paris)KNL1
SOURCE (Princeton)KNL1
Genetics Home Reference (NIH)KNL1
Genomic and cartography
GoldenPath hg19 (UCSC)KNL1  -     chr15:40886447-40954881 +  15q14   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)KNL1  -     15q14   [Description]    (hg38-Dec_2013)
EnsemblKNL1 - 15q14 [CytoView hg19]  KNL1 - 15q14 [CytoView hg38]
Mapping of homologs : NCBIKNL1 [Mapview hg19]  KNL1 [Mapview hg38]
OMIM604321   609173   
Gene and transcription
Genbank (Entrez)AB022190 AB046790 AF173994 AF248041 AF461041
RefSeq transcript (Entrez)NM_144508 NM_170589
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KNL1
Cluster EST : UnigeneHs.181855 [ NCBI ]
CGAP (NCI)Hs.181855
Alternative Splicing GalleryENSG00000137812
Gene ExpressionKNL1 [ NCBI-GEO ]   KNL1 [ EBI - ARRAY_EXPRESS ]   KNL1 [ SEEK ]   KNL1 [ MEM ]
Gene Expression Viewer (FireBrowse)KNL1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)57082
GTEX Portal (Tissue expression)KNL1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8NG31 (Uniprot)
NextProtQ8NG31  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8NG31
Splice isoforms : SwissVarQ8NG31 (Swissvar)
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
DMDM Disease mutations57082
Blocks (Seattle)KNL1
PDB (SRS)3SI5    4A1G    4NF9    4NFA   
PDB (PDBSum)3SI5    4A1G    4NF9    4NFA   
PDB (IMB)3SI5    4A1G    4NF9    4NFA   
PDB (RSDB)3SI5    4A1G    4NF9    4NFA   
Structural Biology KnowledgeBase3SI5    4A1G    4NF9    4NFA   
SCOP (Structural Classification of Proteins)3SI5    4A1G    4NF9    4NFA   
CATH (Classification of proteins structures)3SI5    4A1G    4NF9    4NFA   
Human Protein AtlasENSG00000137812
Peptide AtlasQ8NG31
IPIIPI00220694   IPI00170766   IPI00163659   IPI00747876   IPI01018189   IPI00794405   IPI00981919   IPI00980608   
Protein Interaction databases
IntAct (EBI)Q8NG31
Ontologies - Pathways
Ontology : AmiGOcondensed chromosome kinetochore  acrosomal vesicle  acrosome assembly  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  cytosol  sister chromatid cohesion  mitotic nuclear division  attachment of spindle microtubules to kinetochore  negative regulation of phosphatase activity  CENP-A containing nucleosome assembly  protein localization to kinetochore  cell division  extracellular exosome  spindle assembly checkpoint  
Ontology : EGO-EBIcondensed chromosome kinetochore  acrosomal vesicle  acrosome assembly  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  cytosol  sister chromatid cohesion  mitotic nuclear division  attachment of spindle microtubules to kinetochore  negative regulation of phosphatase activity  CENP-A containing nucleosome assembly  protein localization to kinetochore  cell division  extracellular exosome  spindle assembly checkpoint  
NDEx NetworkKNL1
Atlas of Cancer Signalling NetworkKNL1
Wikipedia pathwaysKNL1
Orthology - Evolution
GeneTree (enSembl)ENSG00000137812
Phylogenetic Trees/Animal Genes : TreeFamKNL1
Homologs : HomoloGeneKNL1
Homology/Alignments : Family Browser (UCSC)KNL1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKNL1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KNL1
Exome Variant ServerKNL1
ExAC (Exome Aggregation Consortium)KNL1 (select the gene name)
Genetic variants : HAPMAP57082
Genomic Variants (DGV)KNL1 [DGVbeta]
DECIPHER (Syndromes)15:40886447-40954881  ENSG00000137812
CONAN: Copy Number AnalysisKNL1 
ICGC Data PortalKNL1 
TCGA Data PortalKNL1 
Broad Tumor PortalKNL1
OASIS PortalKNL1 [ Somatic mutations - Copy number]
Cancer Gene: CensusKNL1 
Mutations and Diseases : HGMDKNL1
LOVD (Leiden Open Variation Database)Whole genome datasets
BioMutasearch KNL1
DgiDB (Drug Gene Interaction Database)KNL1
DoCM (Curated mutations)KNL1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KNL1 (select a term)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM604321    609173   
Genetic Testing Registry KNL1
NextProtQ8NG31 [Medical]
Huge Navigator KNL1 [HugePedia]
snp3D : Map Gene to Disease57082
BioCentury BCIQKNL1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD57082
Chemical/Pharm GKB GenePA142672201
Clinical trialKNL1
canSAR (ICR)KNL1 (select the gene name)
PubMed51 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Oct 26 09:22:58 CEST 2016

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