Alternative titles; symbolsNUF2, S. CEREVISIAE, HOMOLOG OFNUF2RCELL DIVISION CYCLE-ASSOCIATED PROTEIN 1; CDCA1HGNC Approved Gene Symbol: NUF2Cytogenetic location...
Alternative titles; symbols
HGNC Approved Gene Symbol: NUF2
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:163,321,947-163,355,763 (from NCBI)
▼ Cloning and Expression
Wigge and Kilmartin (2001) purified a protein complex from S. cerevisiae that contained various components of the centromere, including Ndc80 (607272) and Nuf2. By database analysis, they identified human NUF2. Immunofluorescence studies showed that both NUF2 and NDC80 localized at the centromeres of mitotic HeLa cells.
Nabetani et al. (2001) cloned human NUF2, which encodes a deduced 464-amino acid coiled-coil protein.
By radiation hybrid analysis, Nabetani et al. (2001) mapped the NUF2 gene to chromosome 1q23.
▼ Gene Function
Nabetani et al. (2001) found that disruption of the Nuf2 gene in S. pombe resulted in defects in chromosome segregation and the spindle checkpoint. In particular, the spindles became elongated but without chromosome segregation. Nabetani et al. (2001) suggested that NUF2 establishes a connection between the spindle and the centromere.
DeLuca et al. (2002) showed that NUF2 specifically functions at kinetochores and acts to stabilize microtubule attachment in HeLa cells. Using RNA interference to block NUF2 translation, they found that spindle formation occurred normally but that kinetochores did not form attachments to active spindle checkpoints. Depletion of NUF2 also induced mitotic cells to undergo cell death. DeLuca et al. (2002) proposed that NUF2 is part of a linker between the kinetochore and tubulin subunits of the spindle.
Liu et al. (2007) demonstrated that NUF2 binds to the C-terminal domain of CENPE (117143) and is required for stabilizing CENPE in the kinetochore. When siRNA blocked NUF2 synthesis, CENPE was no longer detected in the kinetochore and aberrant chromosome segregation occurred. Liu et al. (2007) concluded that both proteins are essential for stable kinetochores and proper chromosome segregation during mitosis.
▼ Molecular Genetics
For discussion of a possible association between variation in the NUF2 gene and microcephaly, vocal cord paralysis, and atrial septal defect, see 611772.0001.
▼ ALLELIC VARIANTS ( 1 Selected Example):
.0001 VARIANT OF UNKNOWN SIGNIFICANCE
This variant is classified as a variant of unknown significance because its contribution to microcephaly, vocal cord paralysis, and atrial septal defect has not been confirmed.
In a 14-year-old Japanese boy with microcephaly, vocal cord paralysis, and atrial septal defect, Uehara et al. (2021) identified heterozygosity for a c.371T-G transversion (c.371T-G, NM_145697.3) in exon 6 of the NUF2 gene, resulting in an ile124-to-ser (I124S) substitution at a residue in the alpha-G helix within the calponin homology domain. The mutation occurred de novo and was not found in the 1000 Genomes Project, HGVD, or gnomAD databases. Western blot of whole-cell lysates from proband lymphoblastoid cell lines (LCLs) revealed markedly reduced NUF2 and NDC80 (607272) levels, by approximately 92% and 78%, respectively, compared to his parents. Immunoprecipitation assays in transfected HeLa or HEK293 cells showed marked inhibition of the interaction between NUF2 and NDC80. In addition, reduced protein levels of NUF2 and NDC80 were shown to result from degradation via the ubiquitin-proteasome system. Chromosome counting in metaphase spreads using patient LCLs revealed that only 15% of patient metaphases had a diploid number of chromosomes, compared to 91% from a control sample, consistent with a malfunctioning kinetochore. There was significant delay in proliferation of proband LCLs compared to control. Patient cells also showed increased levels of micronuclei and an increased rate of formation of multipolar spindles, compared to control cells. Dysmorphic features in the patient included micrognathia, low-set cup-shaped ears, and webbed neck. He experienced transient short stature before the age of 10 years, but growth parameters began resolving at age 11, and at last assessment his height and weight were at -1.0 SD, with occipitofrontal circumference at -3.5 SD. His cognitive development was 'borderline,' but he was able to attend normal school.