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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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CYCLIN O; CCNO

CYCLIN O; CCNO

Alternative titles; symbolsURACIL-DNA GLYCOSYLASE 2; UNG2; UDG2URACIL-DNA GLYCOSYLASE, CYCLIN-LIKEHGNC Approved Gene Symbol: CCNOCytogenetic location: 5q11.2 ...

Alternative titles; symbols

  • URACIL-DNA GLYCOSYLASE 2; UNG2; UDG2
  • URACIL-DNA GLYCOSYLASE, CYCLIN-LIKE

HGNC Approved Gene Symbol: CCNO

Cytogenetic location: 5q11.2 Genomic coordinates (GRCh38): 5:55,231,151-55,233,607 (from NCBI)

▼ Cloning and Expression
Using antibodies directed to uracil-DNA glycosylase purified from HeLa cells, Muller and Caradonna (1991) cloned UDG2 cDNA from a Jurkat T-cell expression library. The deduced 327-amino acid protein has a calculated molecular mass of 35.4 kD. Muller and Caradonna (1991) noted that UDG2 shares no significant amino acid homology with human UNG (191525) or with uracil-DNA glycosylases from yeast, E. coli, or herpes simplex virus. Northern blot analysis detected a 1.6-kb transcript in HeLa cells. Western blot analysis detected a 36-kD protein in human fibroblasts and placenta and in monkey kidney cells, but not in hamster ovary or mouse fibroblasts.

Muller and Caradonna (1993) determined that UDG2 shares significant homology with the conserved cyclin box region of several cyclins, including human cyclin A (CCNA2; 123835).

By immunohistochemical analysis of 3 human cell lines, Caradonna et al. (1996) found that UDG2 localized exclusively in the nucleus.

Wallmeier et al. (2014) found expression of the CCNO gene in the apical cytoplasm of human and mouse respiratory epithelial cells. Expression was increased in murine embryonic respiratory cells compared to adult tissue.

▼ Gene Function
Muller and Caradonna (1991) determined that in vitro translated UDG2 showed significant uracil-DNA glycosylase activity. However, Caradonna (2006) noted that the activity of in vitro translated UDG2 was not as robust as that of the mitochondrial isoform of UNG.

Muller and Caradonna (1993) found that transcription of UDG2 mRNA increased 2- to 3-fold during the G1 phase of the cell cycle in both HeLa cells and human lung fibroblasts. By gel shift assays of cells prepared from various stages of the cell cycle, they demonstrated that a repressor element in the promoter formed several specific DNA complexes during S and G2 phases that were not present during M and G1 phases. Two of the complexes resulted from binding to an inverted cell cycle box (CCB). Immunoprecipitation studies revealed that UDG2 protein levels increased during G1 phase and that the protein turned over during the course of 1 cell cycle.

▼ Gene Structure
Muller and Caradonna (1993) determined that the CCNO gene contains 2 exons and spans about 4.2 kb. The promoter region contains 2 CCB regulatory elements. Deletion analysis revealed a repressor region that contains an inverted CCB and an SP1 (189906)-like binding region.

▼ Mapping
By somatic cell hybrid analysis, Muller and Caradonna (1991) mapped the CCNO gene to chromosome 5.

Gross (2014) mapped the CCNO gene to chromosome 5q11.2 based on an alignment of the CCNO sequence (GenBank BC004877) with the genomic sequence (GRCh37).

▼ Molecular Genetics
In 16 patients from 10 families with primary ciliary dyskinesia-29 (615872), Wallmeier et al. (2014) identified homozygous or compound heterozygous mutations in the CCNO gene (see, e.g., 607752.0001-607752.0006). All but 1 of the mutations resulted in a truncated protein, consistent with a loss of function. Several of the families were consanguineous and 1 was of Kuwaiti origin. The first mutation was found by whole-exome sequencing of 1 family, and the remaining families were identified from a cohort of 53 families with a similar phenotype. All patients had onset in early childhood of recurrent upper and lower respiratory infections, resulting in bronchiectasis and a progressive decrease in lung function. None of the patients had situs inversus. Patient respiratory epithelial cells showed either a complete absence or markedly decreased numbers of cilia, and cultured patient respiratory epithelial cells showed a severe defect in generation of multiple motile cilia, associated with insufficient centriole numbers and decreased basal bodies. Some basal bodies were mislocalized in the cytoplasm, suggesting a basal body migration defect. However, the few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Ccno was found to be a downstream target of mcidas (614086) in Xenopus embryonic skin, a model system for multiciliated cell differentiation, and knockdown of ccno resulted in decreased numbers of mother centrioles and motile cilia. The findings suggested that CCNO functions in a pathway to promote mother centriole amplification and maturation in preparation for apical docking and ciliogenesis.

▼ Animal Model
By parallel analyses of male mice lacking Gemc1 (GMNC; 614448), Mcidas, or Ccno, all of which were infertile, Terre et al. (2019) found that loss of any of these genes impaired formation of multiciliated cells in efferent ducts (EDs), leading to hypocellularity and dilation of seminiferous tubules and rete testes, an indication of fluid backpressure. The fluid backpressure made spermatozoa unable to enter epididymis, resulting in sperm accumulation in EDs and infertility.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 CILIARY DYSKINESIA, PRIMARY, 29
CCNO, 5-BP DUP, 248TGCCC
In 4 affected members of a consanguineous Kuwaiti family with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous 5-bp duplication (c.248_252dupTGCCC) in exon 1 of the CCNO gene, resulting in a frameshift and premature termination (Gly85CysfsTer10). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not present in the 1000 Genomes Project database. One additional patient was found to be compound heterozygous for the c.248_252dupTGCCC mutation and a 2-bp deletion in exon 2 (c.481_482delCT; 607752.0006), resulting in a frameshift and premature termination (Leu161GlyfsTer72).

.0002 CILIARY DYSKINESIA, PRIMARY, 29
CCNO, 5-BP DUP, 258GGCCC
In 4 affected individuals from 2 unrelated consanguineous families with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous 5-bp duplication (c.258_262dupGGCCC) in exon 1 of the CCNO gene, resulting in a frameshift and premature termination (Gln88ArgfsTer7). The mutation segregated with the disorder in the families and was not present in the 1000 Genomes Project database.

In 2 brothers of Irish Traveller descent with CILD29, Casey et al. (2015) identified homozygosity for the same 5-bp duplication (c.258_262dup) in the CCNO gene, which they predicted would result in a Gln88ArgfsTer8 substitution. The mutation, which was found by a combination of homozygosity mapping and exome variant analysis, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family.

.0003 CILIARY DYSKINESIA, PRIMARY, 29
CCNO, 1-BP DEL, 926C
In a patient, born of consanguineous parents, with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous 1-bp deletion (c.926delC) in exon 3 of the CCNO gene, resulting in a frameshift and premature termination (Pro309ArgfsTer17). The mutation segregated with the disorder in the family and was not present in the 1000 Genomes Project database.

.0004 CILIARY DYSKINESIA, PRIMARY, 29
CCNO, GLN321TER
In a patient, born of consanguineous parents, with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous c.961C-T transition in exon 3 of the CCNO gene, resulting in a gln321-to-ter (Q321X) substitution. The mutation segregated with the disorder in the family and was not present in the 1000 Genomes Project database.

.0005 CILIARY DYSKINESIA, PRIMARY, 29
CCNO, 5-BP DUP, 263AGCCC
In 2 sisters, born of consanguineous parents, with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous 5-bp duplication (c.263_267dupAGCCC) in exon 1 of the CCNO gene, resulting in a frameshift and premature termination (Val90SerfsTer5). The mutation segregated with the disorder in the family and was not present in the 1000 Genomes Project database.

.0006 CILIARY DYSKINESIA, PRIMARY, 29
CCNO, 2-BP DEL, 481CT
For discussion of the 2-bp deletion in the CCNO gene (c.481_482delCT) that was found in compound heterozygous state in a patient with primary ciliary dyskinesia-29 (CILD29; 615872) by Wallmeier et al. (2014), see 607752.0001.

Tags: 5q11.2