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HOMEOBOX B13; HOXB13

HOMEOBOX B13; HOXB13

HGNC Approved Gene Symbol: HOXB13Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:48,724,762-48,728,749 (from NCBI)▼ Cloning and ExpressionVer...

HGNC Approved Gene Symbol: HOXB13

Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:48,724,762-48,728,749 (from NCBI)

▼ Cloning and Expression
Vertebrate HOX genes are clustered in 4 unlinked complexes in the genome (HOXA, HOXB, HOXC, and HOXD clusters). Each complex spans about 200 kb and contains 9 to 11 genes, transcribed from the same strand of DNA. The order of the HOX genes along the chromosome correlates with their expression along the anterior/posterior axis of the embryo, suggesting that their organization is integral to their proper regulation. Members of the abdominal B (AbdB) subfamily of HOX genes exhibit posterior domains of expression, including the developing urogenital system, in vertebrates. It was thought that HOXB genes 10 through 13 had been lost in evolution. Using Southwestern screening of a HeLa cell cDNA library, Zeltser et al. (1996) identified HOXB13, a novel member of the AbdB subfamily. Analysis of the cDNA revealed that the HOXB13 gene encodes a 284-amino acid protein, 2 residues shorter than the mouse protein, which was also characterized by Zeltser et al. (1996). The 60-amino acid homeodomain near the C terminus of HOXB13 shares 78 to 83% identity with HOX proteins in paralog group-13 of the AbdB subfamily; 6 of the amino acid differences from other members of this group represent conservative changes. Moreover, HOXB13 shares less than 60% identity with other AbdB-related genes. Using whole-mount in situ hybridization, Zeltser et al. (1996) determined that Hoxb13 was expressed first in the tailbud of embryonic mice and subsequently in the hindgut, urogenital tract, and posterior extent of the spinal cord. It was not expressed in the secondary axes.

During the first 2 trimesters of development, wound healing occurs without scars. Using RT-PCR and sequencing of human fetal fibroblast mRNA, Stelnicki et al. (1998) identified 2 homeobox genes, PRX2 and HOXB13, as being differentially expressed during fetal versus adult wound healing. Both genes were expressed in proliferating fibroblasts and fetal dermis, but not in adult dermis. The protein sequence of HOXB13 differed from that reported by Zeltser et al. (1996) by 1 amino acid alteration, ser211 to cys.

▼ Gene Function
When grown at the air-liquid interface, rat epidermal organotypic cultures stratify and differentiate, producing the same morphologically distinct epidermal layers that are observed in vivo. Mack et al. (2005) found that overexpression of Hoxb13 in these 'lift' cultures increased the overall thickness of the tissue and caused disorganized basal layer, absence of granular layer, and abnormal accumulation of cornified tissue in which numerous nuclei were retained. Overexpression of Hoxb13 also resulted in decreased cell proliferation, increased apoptosis, and reduced expression of epidermal differentiation markers. In both lift and submerged cultures, overexpression of Hoxb13 induced corneocyte formation and elevated transglutaminase (see TGM1; 190195) activity, increasing crosslinking of the cornified envelope. Mack et al. (2005) concluded that HOXB13 functions in epidermal differentiation and likely has a role in skin regeneration and maintenance of normal barrier function.

Miao et al. (2007) found that knockdown of HOXB13 by RNA interference in human ovarian cancer cell lines was associated with reduced cell proliferation. Conversely, ectopic expression of HOXB13 transformed p53 (TP53; 191170) -/- mouse embryonic fibroblasts and promoted cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines containing genetic alterations in p53, Myc (190080), and Ras (HRAS; 190020). HOXB13 collaborated with activated Ras to markedly promote tumor growth in vivo in nude mice and conferred resistance to tamoxifen-mediated apoptosis in mouse ovarian cancer cells in culture. Miao et al. (2007) concluded that HOXB13 has a proproliferative and prosurvival role in ovarian cancer.

Norris et al. (2009) stated that HOXB13 interacts with androgen receptor (AR; 313700) and plays an essential role in prostate development. They found that HOXB13 played multiple roles in determining the response of prostate cancer cells to androgens. HOXB13 interacted with the DNA-binding domain of AR and inhibited transcription of genes containing an androgen response element (ARE). In contrast, the AR-HOXB13 complex conferred androgen responsiveness to promoters containing a specific HOXB13 response element. HOXB13 and AR also synergized to enhance transcription of genes containing a HOX element juxtaposed to an ARE. Norris et al. (2009) concluded that HOXB13 functions as a licensing factor for both AR and AR coregulator recruitment to chromatin.

▼ Gene Structure
Zeltser et al. (1996) determined that the HOXB13 gene contains 2 exons. It is separated from HOXB9 by 70 kb, but is transcribed in the same orientation as the other HOXB genes.

▼ Mapping
By FISH, Stelnicki et al. (1998) mapped the HOXB13 gene to human chromosome 17q21.2, where other HOXB genes are clustered. By somatic cell hybrid analysis, Zeltser et al. (1996) mapped the mouse Hoxb13 gene to chromosome 11.

▼ Molecular Genetics
To identify a prostate cancer susceptibility gene in the 17q21-q22 region (HPC9; 610997), Ewing et al. (2012) sequenced 2,009 exons from 202 genes in germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. They then tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from 4 families were discovered to have a rare but recurrent mutation, G84E (rs138213197; 604607.0001), in HOXB13, a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these 4 families carried the mutation. At the time of the analysis the G84E mutation was not reported in dbSNP or in the NCBI 1000 Genomes sequencing project, which included 1,094 subjects, 381 of European descent. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5,083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1,401 control subjects (0.1%) (P = 8.5 x 10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0 x 10(-6)). Ewing et al. (2012) concluded that this novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Ewing et al. (2012) identified 4 additional rare HOXB13 mutations, 1 in the same MEIS interaction domain where the G84E mutation is located, 1 in a second MEIS binding domain, and 2 in the homeodomain.

Huang et al. (2014) found that a prostate cancer risk-associated SNP on chromosome 6q22, rs339331, lies within an evolutionarily conserved region in intron 4 of the transcription factor RFX6 gene (612659) that functions as a HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration, and invasion. Clinical data indicated that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis, and risk of biochemical relapse. Huang et al. (2014) observed a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. The authors concluded that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.

Associations Pending Confirmation

For discussion of a possible association between variation in the HOXB13 gene and breast cancer susceptibility, see 114480.

▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001 PROSTATE CANCER, HEREDITARY, 9
HOXB13, GLY84GLU (rs138213197)
To identify a prostate cancer susceptibility gene in the 17q21-q22 region (HPC9; 610997), Ewing et al. (2012) sequenced 2,009 exons from 202 genes in germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. They then tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from 4 families were discovered to have a rare but recurrent mutation, G84E (rs138213197), in HOXB13. All 18 men with prostate cancer and available DNA in these 4 families carried the mutation. At the time of the analysis the G84E mutation was not reported in dbSNP or in the NCBI 1000 Genomes sequencing project (May 2011), which included 1,094 subjects, 381 of European descent. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5,083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1,401 control subjects (0.1%) (P = 8.5 x 10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0 x 10(-6)).

Hamosh (2018) noted that the G84E mutation in the HOXB13 gene was present in 530 of 275,718 alleles and in 2 homozygotes in the gnomAD database (October 23, 2018).

Tags: 17q21.32