Alternative titles; symbolsUDP GLYCOSYLTRANSFERASE 2 FAMILY, MEMBER B17UDP GLUCURONOSYLTRANSFERASE 2 FAMILY, MEMBER B17HGNC Approved Gene Symbol: UGT2B17Cytogene...
Alternative titles; symbols
HGNC Approved Gene Symbol: UGT2B17
Cytogenetic location: 4q13.2 Genomic coordinates (GRCh38): 4:68,537,172-68,576,321 (from NCBI)
UGT2B17 belongs to the family of UDP-glucuronosyltransferases (UGTs; EC 184.108.40.206), enzymes that catalyze the transfer of glucuronic acid from uridine diphosphoglucuronic acid to a variety of substrates, including steroid hormones.
▼ Cloning and Expression
Beaulieu et al. (1996) cloned the cDNA corresponding to a novel UGT, termed UGT2B17, from a human prostate cDNA library. Sequence analysis predicted that the UGT2B17 gene encodes a 530-amino acid polypeptide with an 8-amino acid signal sequence and a single membrane-spanning domain. The amino acid sequence of UGT2B17 is 94% identical to that of UGT2B15 (600069). RT-PCR analysis revealed that UGT2B17 is expressed in various tissues, including liver, testis, uterus, mammary gland, and prostate. cell line.
▼ Gene Structure
Beaulieu et al. (1997) reported that the UGT2B17 gene contains 6 exons and spans approximately 30 kb.
By fluorescence in situ hybridization, Beaulieu et al. (1997) mapped the UGT2B17 gene to chromosome 4q13. This region contains a cluster of 3 other UGT2B genes (see UGT2B7; 600068).
▼ Gene Function
Beaulieu et al. (1996) expressed UGT2B17 in HK293 cells and tested its enzymatic activity against more than 60 substrates. Its major substrates, in order of reactivity, were eugenol, 4-methylumbelliferone, dihydrotestosterone, 3-alpha-diol, testosterone, and androsterone.
Glucuronidation is thought to inactivate steroids. Dihydrotestosterone (DHT) and epidermal growth factor (EGF; 131530) have been shown to inhibit the glucuronidation of androgens in the prostate (Beaulieu et al., 1997). By use of a reporter gene construct, Beaulieu et al. (1997) found that a 2.9-kb fragment from the 5-prime region of the UGT2B17 gene was sufficient to confer significant basal transcriptional activity, and showed that UGT2B17 expression was regulated by androgens and EGF. The authors stated that their results demonstrated regulation of the UGT2B17 gene by physiologic effectors of the human prostate and supported the hypothesis that UGT enzymes are involved in steroid metabolism in extrahepatic tissues.
Although it is widely recognized that the liver is a major site of steroid glucuronidation, RT-PCR analysis had shown the expression of UGT2B transcripts in extrahepatic steroid target tissues such as the prostate (Hum et al., 1999). Measurement of androgen metabolites in human prostate revealed high levels of C19 steroid glucuronides such as androsterone glucuronide and 3-alpha-diol glucuronide, thus suggesting an important role for UGT2B enzymes in androgen metabolism (Belanger et al., 1990). To investigate the role of UGT2B enzymes in the catabolism of androgen in prostatic target cells and to determine their potential as effective hormonal signal terminators, Barbier et al. (2000) analyzed the cellular localization of UGT2B expression in the human prostate. In situ hybridization studies demonstrated the presence of UGT2B transcripts in epithelial cells lining the acinii. All basal cells were intensively labeled, whereas the luminal secretory cells were moderately labeled. Using a specific anti-UGT2B17 antibody, the expression of this androsterone-conjugating UGT enzyme was found exclusively in basal cells of the epithelium. The authors demonstrated the expression of androgen-conjugating UGT2B enzymes in human prostatic epithelium and showed for the first time a cell type-specific expression of a UGT2B isoform.
▼ Molecular Genetics
Using cDNA expression cloning, Murata et al. (2003) identified a novel minor histocompatibility antigen encoded by UGT2B17 that resulted not from a polymorphism, but from homozygous deletion of UGT2B17 in the HLA-identical sib donor of stem cells. Target cells transfected with a construct encoding a peptide in the central portion of UGT2B17 and presented by HLA-A29 were recognized by CD8-positive cytotoxic lymphocytes (CTLs) cloned from the peripheral blood of the recipient after stem cell transplantation and the onset of graft-versus-host disease (GVHD; see 614395). PCR analysis with multiple primer pairs confirmed the absence of UGT2B17 expression in donor cells, but not recipient cells. UGT2B17 gene deletion was found in 4 (11%) of 36 control individuals. RT-PCR and dot blot analysis detected abundant UGT2B17 expression in liver, colon, small intestine, and pancreas, tissues frequently targeted in GVHD, with little or no expression in other tissues. Pretransplant recipient dendritic and B cells, but not T cells, expressed UGT2B17 and induced IFNG (147570) expression by specific CTLs. Murata et al. (2003) concluded that differential protein expression as a consequence of gene deletion is a mechanism for generating minor histocompatibility antigens.
The UGT2B17 and UGT2B15 genes share 95% sequence identity and appear to represent a tandem duplication. Using gene-specific primers, Wilson et al. (2004) demonstrated that a 150-kb genomic interval (601903.0001) spanning the entire UGT2B17 gene was absent in some human DNA samples, indicating that UGT2B17 is present in the human genome as a deletion polymorphism linked to UGT2B15. The UGT2B17 deletion polymorphism showed mendelian segregation and allele frequencies that differed between African Americans and Caucasians.
The UGT2B17 gene varies in copy number from 0 to 2 per individual and also differs in mean number between populations from Africa, Europe, and East Asia. Xue et al. (2008) showed that such a high degree of geographic variation is unusual and investigated its evolutionary history. They reinterpreted the reference sequence in this region of the genome, which was misassembled from the 2 different alleles separated by an artifactual gap. A corrected assembly identified the polymorphism as a 117-kb deletion arising by nonallelic homologous recombination between approximately 4.9-kb segmental duplications and allowed the deletion breakpoint to be identified. Xue et al. (2008) resequenced 12 kb of DNA spanning the breakpoint in 91 humans from 3 HapMap and 1 extended HapMap populations and 1 chimpanzee. Diversity was unusually high and the time to the most recent common ancestor was estimated at 2.4 to 3.0 million years by 2 different methods, with evidence of balancing selection in Europe. In contrast, diversity was low in East Asia where a single haplotype predominated, suggesting positive selection for the deletion in that part of the world.
In a case-control study involving Chinese individuals with osteoporosis-related hip fracture (BMND12; 612560), Yang et al. (2008) identified an association between copy number variation (CNV) of the UGT2B17 gene resulting from the 150-kb polymorphic deletion and osteoporotic fracture. In an independent sample of Chinese and Caucasian individuals, they found consistently significant association between UGT2B17 CNV and major risk factors for osteoporotic fracture. Individuals without UGT2B17 were shown to have significantly higher concentrations of testosterone and estradiol. Yang et al. (2008) concluded that UGT2B17 CNV plays an important role in the pathogenesis of osteoporosis.
Analyzing common gene deletions in 3 hematopoietic stem cell transplantation (HSCT) cohorts, McCarroll et al. (2009) found that the risk of graft-versus-host disease (GVHD) was greater when the donor and recipient were mismatched for homozygous deletion of the UGT2B17 gene (odds ratio, 2.5; p = 0.0005). Increased risk was confined to the group of transplants in which donors were UGT2B17-negative and recipients were UGT2B17-positive. McCarroll et al. (2009) suggested that human genome structural variation may be involved in diseases of alloimmunity.
Testosterone abuse is conventionally assessed by the urinary testosterone/epitestosterone (T/E) ratio, levels above 4.0 being considered suspicious. To investigate the effect of the UGT2B17 ins/del polymorphism on testosterone excretion and the T/E ratio after testosterone administration, Schulze et al. (2008) administered a single intramuscular dose of 500 mg testosterone enanthate to 55 healthy male volunteers with either 2, 1, or no insertion alleles (ins/ins, ins/del, or del/del) of the UGT2B17 gene. Urinary excretion of testosterone glucuronide (TG) after dose and the T/E ratio during 15 days were calculated. Schulze et al. (2008) found that the degree and rate of increase in the TG excretion rate were highly dependent on UGT2B17 genotype, with a 20-fold higher average maximum increase in the ins/ins group compared with the del/del group. Of the del/del subjects, 40% never reached the T/E ratio of 4.0 on any of the 15 days after the dose. When differentiated cutoff levels for the del/del (1.0) and the other genotypes (6.0) were applied, the sensitivity increased substantially for the del/del group, and false positives in the other genotypes were eliminated. The authors concluded that consideration of the genetic variation in disposition of androgens will improve the sensitivity and specificity of the testosterone doping test.
▼ Population Genetics
Jakobsson et al. (2006) found that the UGT2B17 del/del genotype was much more common among 74 Korean men (66.7%) than among 122 Swedish men (9.3%).
Using DNA from 100 healthy unrelated Caucasian volunteers, Menard et al. (2009) characterized the common UGT2B17 and UGT2B28 (606497) deletions and observed that CNVs of UGT2B17 and UGT2B28 occur in Caucasians at 27% and 13.5%, respectively, with 43% carrying 2 copies of both genes and 57% harboring at least 1 deletion. CNVs of both UGT2B17 and UGT2B28, with cooccurrence of the D85Y polymorphism (rs1902023) in the UGT2B15 gene (600069), generate 7 distinct haplotypes. The authors concluded that analyzing CNV of UGT2B17 without evaluating UGT2B28 and the D85Y variant in UGT2B15 may over- or underestimate the phenotypic impact of each gene.
By analyzing short-read mapping depth for 159 human genomes, Sudmant et al. (2010) demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kb pairs, ranging from 0 to 48 copies. Sudmant et al. (2010) identified 4.1 million 'singly unique nucleotide' positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identified human-specific expansions in genes associated with brain development, such as GPRIN2 (611240) and SRGAP2 (606524), which have been implicated in neurite outgrowth and branching. Also included were the brain-specific HYDIN2 gene (610813), associated with micro- and macrocephaly; DRD5 (126453), a dopamine D5 receptor; and the GTF2I (601679) transcription factors, whose deletion has been associated with visual-spatial and sociability deficits among Williams-Beuren syndrome (194050) patients, among others. The data of Sudmant et al. (2010) also revealed extensive population genetic diversity, especially among the genes NPEPPS (606793), UGT2B17, and NBPF1 (610501), as well as LILRA3 (604818), which is the most highly stratified gene by copy number in the human genome. In addition, Sudmant et al. (2010) detected signatures consistent with gene conversion in the human species.
▼ ALLELIC VARIANTS ( 1 Selected Example):
.0001 BONE MINERAL DENSITY QUANTITATIVE TRAIT LOCUS 12
UGT2B17, 150-KB DEL
In a case-control genomewide analysis of copy number variation (CNV) in 350 elderly Chinese individuals with osteoporosis-related hip fracture (BMND12; 612560) and 350 geography- and age-matched controls, Yang et al. (2008) found CNV on chromosome 4q13.2 to be strongly associated with osteoporotic fracture (p = 2.0 x 10(-4), corrected p = 0.02; odds ratio = 1.73). Using PCR and electrophoresis as well as real-time PCR in 60 Chinese individuals, 20 for each copy-number genotype predicted by the Affymetrix copy number analysis tool (CNAT), the authors identified a 150-kb deleted interval at chromosome 4q13.2 spanning the entire UGT2B17 gene. The authors replicated the association between UGT2B17 CNV and osteoporotic fracture in an independent Chinese sample of 399 cases with osteoporosis-related hip fracture and 400 age-matched controls (p = 6.34 x 10(-3)), and demonstrated an increased risk of osteoporotic fracture in individuals with an existing UGT2B17 gene (odds ratio = 1.58; p = 0.01). Yang et al. (2008) also found consistently significant association between UGT2B17 CNV and major risk factors for osteoporotic fracture in an independent sample of 689 Chinese and 1,000 Caucasian individuals, and in an independent sample of 236 young Chinese males, they demonstrated that individuals without UGT2B17 had significantly higher concentrations of testosterone and estradiol.