Alternative titles; symbols
HGNC Approved Gene Symbol: SLCO2A1
Cytogenetic location: 3q22.1-q22.2 Genomic coordinates (GRCh38): 3:133,932,701-134,029,925 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q22.1-q22.2 | Hypertrophic osteoarthropathy, primary, autosomal dominant | 167100 | Autosomal dominant | 3 |
| PHOAR2-enteropathy syndrome | 614441 | Autosomal recessive | 3 |
SLCO2A1 encodes a prostaglandin transporter (summary by Seki et al., 2022).
Kanai et al. (1995) cloned rat Slco2a1, which they called Pgt.
Lu et al. (1996) screened a human kidney cDNA library and isolated human PGT. The deduced 643-amino acid protein shares 82% identity with the rat protein. It contains 12 putative transmembrane domains and 3 N-glycosylation sites. Northern blot analysis detected wide PGT distribution, with transcripts ranging from 2.1 to 10 kb. Transcripts of 4.4 to 5.1 kb, often appearing as a doublet, were expressed in most adult tissues and all fetal tissues examined. Lu et al. (1996) noted that the tissue distribution of PGT transcripts was substantially broader, and the variety of PGT transcripts was greater, in human compared with rat.
By PCR-based monochromosomal somatic cell hybrid mapping and fluorescence in situ hybridization, Lu and Schuster (1998) mapped the PGT gene to chromosome 3q21.
Stumpf (2021) mapped the SLCO2A1 gene to chromosome 3q22.1-q22.2 based on an alignment of the SLCO2A1 sequence (GenBank BC051347) with the genomic sequence (GRCh38).
At physiologic pH, prostaglandins (PGs) traverse biologic membranes poorly. Accordingly, PG transport is carrier-mediated in many tissues, including lung, choroid plexus, liver, anterior chamber of the eye, vagina and uterus, and placenta. Kanai et al. (1995) postulated 3 possible roles for PGT. First, PGT might mediate the efflux of newly synthesized PGs from cells. Second, PGT might mediate epithelial PG transport. A third possible role of PGT is that of mediating PG clearance and degradation. Lu et al. (1996) favored the clearance role for PGT. They expressed a full-length human PGT cDNA clone in cultured cells and found that both rat and human PGT transported PGD2, as well as PGE1, PGE2, and PGF2a. Compared with rat Pgt, human PGT showed higher affinity for thromboxane-2.
PHOAR2-Enteropathy Syndrome
In 3 unrelated Han Chinese male probands with primary hypertrophic osteoarthropathy (PHO), including 1 who also experienced gastric ulcer and gastrointestinal hemorrhage (PHOAR2E syndrome; 614441), Zhang et al. (2012) identified homozygosity or compound heterozygosity for mutations in the SLCO2A1 gene (601460.0001-601460.0005) that segregated with disease in each family and were not found in 250 ethnically matched controls.
In 2 unrelated families with PHOAR2-enteropathy syndrome, Seifert et al. (2012) identified homozygosity for different homozygous mutations in the SLCO2A1 gene (see, e.g., 601460.0006). In another family in which the proband had only digital clubbing, they identified heterozygosity for a nonsense mutation in SLCO2A1 (R252X; 601460.0007).
In probands from 12 unrelated PHO families of diverse ethnicities, Diggle et al. (2012) identified homozygosity or compound heterozygosity for 15 different mutations in the SLCO2A1 gene, including 3 nonsense, 8 missense, and 4 splice junction mutations (see, e.g., 601460.0004 and 601460.0008-601460.0010). The authors noted that mild features, usually digital clubbing, were sometimes apparent in older heterozygous mutation carriers.
In 6 patients from 4 unrelated families with PHO, including 2 Indian and 2 Japanese families, Busch et al. (2012) identified homozygous or compound heterozygous mutations in the SLCO2A1 gene (see, e.g., 601460.0005 and 601460.0017-601460.0018).
In 5 unrelated Chinese male patients with PHO, who were known to be negative for mutation in the HPGD gene (601688), Zhang et al. (2013) identified biallelic mutations in the SLCO2A1 gene (see, e.g., 601460.0003-601460.0004 and 601460.0019). All 5 probands experienced recurrent watery diarrhea, and the proband in family 1 and 2 of his 4 sisters presented severe anemia and hypoalbuminemia (see 601460.0019).
In 18 Japanese patients diagnosed with chronic nonspecific multiple ulcers of the small intestine (CNSU), 11 of whom also exhibited features of PHO, Umeno et al. (2015) identified biallelic variants in the SLCO2A1 gene (601460.0004, 601460.0005, 601460.0013, 601460.0020, 601460.0021, 601460.0023, and 601460.0026). Functional analysis in transfected HEK293 cells demonstrated that none of the 6 mutants tested was able to take up prostaglandin (PGE), indicating loss of function as a PGE transporter.
In 3 male patients from 2 Korean families with PHO and watery diarrhea, Lee et al. (2016) identified biallelic mutations in the SLCO2A1 gene in both families: in one family, the proband was compound heterozygous for a previously reported splicing mutation (c.940+1G-A; 601460.0005) and a nonsense mutation (R603X; 601460.0013), whereas in the other family, the 2 affected brothers were homozygous for the c.940+1G-A splicing mutation.
In 33 Chinese men with PHO, 19 (58%) of whom experienced anemia, gastrointestinal hemorrhage, and/or watery diarrhea, Li et al. (2017) identified homozygosity or compound heterozygosity for mutations in the SLCO2A1 gene (see, e.g., 601460.0002, 601460.0004, 601460.0011, 601460.0013-601460.0015, 601460.0021, 601460.0022, and 601460.0024-601460.0033). Noting that fewer females are affected with PHOAR2E, and that they generally show an atypical PHO phenotype with less severe skin and skeletal symptoms, the authors explored the role of sex hormones in SLCO2A1 regulation; however, they found no statistically significant relationships between urinary PGE2 or PGEM and serum sex hormones.
Umeno et al. (2018) reviewed 46 Japanese patients, 33 female and 13 male, from 43 families that were ascertained by a nationwide survey recruiting for patients with CNSU and mutation in the SLCO2A1 gene. The most frequent mutation identified was c.940+1G-A (601460.0005), which was present in 50 (54%) of 92 alleles; the second most common mutation was R603X (601460.0013), present in 20 (22%) alleles. Noting that their survey reconfirmed the female predominance in gastrointestinal involvement, whereas features of PHO were more frequent and more severe in male patients, with none of their female patients showing pachydermia, the authors suggested that sex-related modifier genes or hormones might account for observed differences in major clinical manifestations according to gender.
In 46 Korean patients with CNSU, Hong et al. (2022) performed Sanger sequencing of the SLCO2A1 gene, and identified biallelic mutations in 12 female and 2 male patients from 11 families, all of whom were homozygous or compound heterozygous for the previously reported c.940+1G-A splice site mutation (601460.0005) and/or R603X (601460.0013). Features of PHO were present in 5 (36%) of the patients, and 2 men and 1 woman exhibited all 3 major PHO manifestations (digital clubbing, pachydermia, and periostosis).
In 2 unrelated Mexican men with PHO and enteropathy, Kimball et al. (2024) analyzed the HPGD and SLCO2A1 genes, and identified homozygosity for different mutations in the SLCO2A1 gene: patient 1 was homozygous for a previously reported PHOAR2-enteropathy-associated missense mutation (G183R; 601460.0026), and patient 2 was homozygous for a novel 1-bp deletion (601460.0034).
Autosomal Dominant Primary Hypertrophic Osteoarthropathy
Zhang et al. (2013) studied 7 Chinese families with PHO, including 5 in which affected individuals carried biallelic mutations in the SLCO2A1 gene (see, e.g., 601460.0003). However, 2 of the families represented autosomal dominant PHO (PHOAD; 167100), with probands who were heterozygous for mutations in SLCO2A1 (see, e.g., 601460.0011). Incomplete penetrance was observed in both PHOAD families, as the mutations were inherited from an unaffected father and mother, respectively.
In a 4-generation French Canadian family with PHOAD with digital clubbing restricted to male members, Guda et al. (2014) identified heterozygosity for the G104X mutation (601460.0010) in the SLCO2A1 gene, which had previously been identified in homozygosity by Diggle et al. (2012) in an Italian patient with PHO. In the French Canadian family, colonic neoplasia was also common and showed early onset in males. Sessile serrated adenomas also arose in 2 sisters of the proband who carried the G104X mutation, at ages 54 and 57 years, respectively. Review of family clinical records and genetic testing showed no evidence of familial adenomatous polyposis (FAP; see 175100) or hereditary nonpolyposis colorectal cancer (HNPCC; see 120435). Noting that aspirin, a known inhibitor of prostaglandin production, had been associated with a reduced risk of serrated polyps, Guda et al. (2014) suggested that prostaglandins might play a role in the pathogenesis of sessile serrated adenomas.
In 3 Korean brothers (family 1) with PHOAD, Lee et al. (2016) identified heterozygosity for a missense mutation in the SLCO2A1 gene (I101S; 601460.0012). DNA from their unaffected parents was unavailable. In addition, the authors studied 3 male patients from 2 Korean families with PHOAR, whose features included PDA and other cardiac anomalies, and identified biallelic mutations in the SLCO2A1 gene in both families: in family 2, the proband was compound heterozygous for a previously reported splicing mutation (c.940+1G-A; 601460.0005) and a nonsense mutation (R603X; 601460.0013), whereas in family 3, the 2 affected brothers were homozygous for the c.940+1G-A splicing mutation. All parents were clinically unaffected, and segregation was confirmed in 3 of them, but DNA was unavailable from the mother in family 3.
Xu et al. (2021) reported 7 Chinese families with PHOAD and heterozygous SLCO2A1 mutations, and 5 with PHOAR2 and biallelic SLCO2A1 mutations, including some mutations that were the same in dominant and recessive families (see, e.g., 601460.0004, 601460.0013, and 601460.0015). All of the SLCO2A1 mutations were absent or had an extremely low frequency in the ExAC and/or gnomAD databases, and none was found in 250 Chinese controls. Incomplete penetrance was observed, with an overall penetrance rate of 83%, and penetrance was higher in males (100%) than in females (58%).
Functional Characterization of SLCO2A1 Mutations
Seki et al. (2022) found that 10 of 11 mutations in SLCO2A1 found in patients with chronic enteropathy, including R603X (601460.0013), 830insT (601460.0006), and 940+1G-A (601460.0005), resulted in decreased or complete loss of PGE2 transport ability when the recombinant protein was expressed in Xenopus oocytes.
Xu et al. (2021) studied 7 Chinese probands with PHOAD and compared their phenotype with that of 50 patients with PHOAR2. Similarities included onset around the time of puberty, with incomplete penetrance more commonly seen in female patients. However, signs and symptoms of PHO were milder in PHOAD than in PHOAR2 patients, including less severe pachydermia and periostosis, and less frequent cutis verticis gyrata, acne, arthralgia, and anemia. In addition, the median urinary PGE2 level in PHOAD probands was approximately half of that seen in PHOAR2 patients.
Kimball et al. (2024) reviewed 232 published cases with molecularly confirmed PHOAR2 and/or 'chronic enteropathy associated with SLCO2A1' (CEAS), comprising 109 different variants in the SLCO2A1 gene. Information regarding the presence or absence of gastrointestinal symptoms was available for 173 cases, of which 113 (65%) had at least 1 clinical finding suggestive of chronic enteropathy. Phenotype was analyzed in 159 cases, of which 83 (52%) involved combined PHOAR2 and enteropathy, 60 (38%) presented isolated PHOAR2, and 16 (10%) were isolated enteropathy cases. Isolated PHOAR2 was found exclusively in male patients, and 14 of the 16 patients with isolated enteropathy were female. The authors found a statistically significant association between SLCO2A1 variants located in intron 7 or exons 12 and 13 and the development of enteropathy. In addition, the proportion of missense variants was greater in isolated PHOAR2 than in either isolated enteropathy or combined PHOAR2/enteropathy, whereas nonsense and splice site variants were more prevalent in the enteropathy group. The authors noted that further investigation was needed to elucidate the underlying pathophysiologic mechanisms for the differences in presentation.
Chang et al. (2010) generated Pgt-deficient mice and observed that no knockout (Pgt -/-) mice survived beyond postnatal day 1, and no hypomorphic (Pgt neo/neo) mice survived beyond postnatal day 2. Necropsy revealed patent ductus arteriosus with normal intimal thickening but dilated cardiac chambers. Both knockout and hypomorphic mice could be rescued through the postnatal period by giving the mother indomethacin before birth. Rescued mice grew normally and had no abnormalities by gross or microscopic postmortem analyses. Rescued adult Pgt -/- had lower plasma PGE(2) metabolite levels and higher urinary PGE(2) excretion rates than wildtype mice. Chang et al. (2010) concluded that PGT plays a critical role in closure of the ductus arteriosus after birth by ensuring a reduction in local and/or circulating prostaglandin E2 levels.
In a Han Chinese man (family 1) with primary hypertrophic osteoarthropathy (PHOAR2E; 614441), Zhang et al. (2012) identified homozygosity for a G-A transition at the invariant -1 position of the acceptor site of intron 1 (c.97-1G-A, NM_005630.2) in the SLCO2A1 gene, resulting in skipping of exon 2 and loss of 46 residues. His unaffected parents and 4 other unaffected relatives were heterozygous for the mutation, which was not found in 250 ethnically matched controls.
In a Han Chinese man (family 2) with primary hypertrophic osteoarthropathy (PHO), who also experienced gastric ulcer and gastrointestinal hemorrhage (PHOAR2E; 614441), Zhang et al. (2012) identified compound heterozygosity for a c.764G-A transition (c.764G-A, NM_005630.2) in exon 6 of the SLCO2A1 gene, resulting in a gly255-to-glu (G255E) substitution at a highly conserved residue, and a 1-bp deletion (1634delA) in exon 12 (601460.0003), causing a frameshift predicted to result in a premature termination codon and loss of the eleventh and twelfth transmembrane domains. His unaffected parents and an unaffected daughter, as well as 3 other unaffected relatives, were each heterozygous for one of the mutations, neither of which was found in 250 ethnically matched controls.
In a 24-year-old Chinese man (P11) with PHO, Li et al. (2017) identified compound heterozygosity for the G255E substitution in SLCO2A1, and a c.795G-A transition in exon 6, resulting in a trp253-to-ter (W253X; 601460.0030) substitution. Gastrointestinal symptoms were not reported in this patient. The G255E substitution was not found in the ExAC database.
For discussion of the 1-bp deletion in the SLCO2A1 gene (c.1634delA, NM_005630.2) that was found in compound heterozygous state in a Han Chinese man (family 2) with primary hypertrophic osteoarthropathy, who also experienced gastric ulcer and gastrointestinal hemorrhage (PHOAR2E; 614441) by Zhang et al. (2012), see 601460.0002.
In a 26-year-old Chinese man (family 5) with PHOAR2E who had digital clubbing, facial furrowing, periosteal overgrowth of the long bones, and recurrent episodes of watery diarrhea, Zhang et al. (2013) identified compound heterozygosity for the previously reported 1-bp deletion (c.1634delA) in exon 12 of the SLCO2A1 gene, causing a frameshift predicted to result in a premature termination codon (Asn545ThrfsTer5), and the previously reported G222R missense mutation (601460.0004). His unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 125 controls.
PHOAR2-Enteropathy Syndrome
In a 21-year-old Han Chinese man (family 3) with primary hypertrophic osteoarthropathy (PHOAR2E; 614441), Zhang et al. (2012) identified compound heterozygosity for a c.664G-A transition (c.664G-A, NM_005630.2) in exon 5 of the SLCO2A1 gene, resulting in a gly222-to-arg (G222R) substitution at a highly conserved residue, and a G-A transition at the invariant +1 position of the acceptor site of intron 7 (c.940+1G-A), predicted to result in skipping of exon 7, leading to a frameshift and premature termination codon (601460.0005). His unaffected parents were each heterozygous for 1 of the mutations; neither mutation was found in 250 ethnically matched controls.
In a North African patient (family B) who was diagnosed with PHO at 16 years of age and developed anemia and was found to have myelofibrosis at age 21, Diggle et al. (2012) identified homozygosity for the G222R mutation in the SLCO2A1 gene. The patient had an affected brother who was not studied.
For discussion of the G222R mutation in SLCO2A1 that was found in compound heterozygous state in a patient (family 5) with PHO and recurrent episodes of watery diarrhea by Zhang et al. (2013), see 601460.0003.
In a 63-year-old Japanese man (patient 12) with chronic nonspecific ulcers (CNSU) of the jejunum and ileum, who also fulfilled the criteria for PHO, Umeno et al. (2015) identified homozygosity for the G222R mutation in the SLCO2A1 gene. In 2 Japanese sisters (patients 4 and 5, family D), who had CNSU of the stomach, duodenum, and ileum, and also exhibited acne, large joint arthralgias, and hyperhidrosis, the authors identified compound heterozygosity for the G222R substitution and a nonsense mutation (R603X; 601460.0013). Familial segregation was not reported, but neither mutation was found in 747 Japanese controls. Functional analysis in transfected HEK293 cells demonstrated that the G222R and R603X mutants were unable to take up PGE, indicating loss of function as a PGE transporter.
Xu et al. (2021) reported a Chinese man (proband of family 8) with PHOAR2E who was compound heterozygous for the G222R substitution and a c.621C-A transversion in exon 4 of the SLCO2A1 gene, resulting in a tyr207-to-ter (Y207X; 601460.0014) substitution. Neither mutation was found in 250 Chinese controls. This proband, who was previously studied as P35 by Li et al. (2017), was noted by them to be 51 years old and to have pachydermia, digital clubbing, periostosis, arthralgia, and watery diarrhea; Xu et al. (2021) noted that his father, who was heterozygous for the G222R variant, fulfilled the 3 diagnostic criteria for PHO, with pachydermia, digital clubbing, and periostosis, as well as joint swelling. His mother, who was heterozygous for the Y207X variant, exhibited only digital clubbing.
Autosomal Dominant Primary Hypertrophic Osteoarthropathy
In a Chinese father and son (family 2) with autosomal dominant PHO (PHOAD; 167100), Xu et al. (2021) reported heterozygosity for the G222R mutation (c.664G-A, NM_005630.2) in the SLCO2A1 gene. The 30-year-old proband, who was previously studied as P31 by Li et al. (2017), had digital clubbing and periostosis, whereas his father exhibited digital clubbing only. Li et al. (2017) reported that this proband had watery diarrhea.
For discussion of the splice site mutation in the SLCO2A1 gene (c.940+1G-A, NM_005630.2) that was found in compound heterozygous state in a 21-year-old Han Chinese man (family 3) with primary hypertrophic osteoarthropathy (PHOAR2E; 614441) by Zhang et al. (2012), see 601460.0004.
In 2 Japanese brothers (family 4) with primary hypertrophic osteoarthropathy (PHO), Busch et al. (2012) identified homozygosity for the c.940+1G-A mutation in the SLCO2A1 gene. In an unrelated 53-year-old Japanese man with PHO (family 3), they identified compound heterozygosity for the splice site mutation and a c.1668G-C transversion in exon 12 of the SLCO2A1 gene, resulting in a gln556-to-his (Q556H; 601460.0017) substitution at a conserved residue. The presence or absence of gastrointestinal symptoms was not reported in these patients. Noting that their patients harbored identical SNPs, mostly likely in cis, the authors suggested that the c.940+1G-A variant might represent an ancient founder allele rather than a recurrent mutation.
In 9 Japanese patients diagnosed with chronic nonspecific ulcers (CNSU) of the small intestine, including 7 women and 2 men, Umeno et al. (2015) identified homozygosity for the c.940+1G-A mutation (c.940+1G-A, NM_005630) in the SLCO2A1 gene. One of the homozygotes was a 70-year-old man (patient 16) with CNSU of the duodenum and ileum, who also fulfilled the criteria for PHO. The mutation was found in heterozygous state in 3 of 747 Japanese controls, for a minor allele frequency of 0.0022, which the authors noted was similar to the MAF for the Japanese population in the HGVD database. Immunofluorescence staining of the small intestine from 2 homozygous patients did not detect any SLCO2A1 protein in the vascular endothelial cells of the patients, consistent with lack of expression of the mutant protein. The authors also identified 3 Japanese CNSU patients who were compound heterozygous for the c.940+1G-A transition and another mutation in the SLCO2A1 gene: an 18-year-old woman (patient 15) with CNSU of the duodenum and ileum, who did not present signs of PHO, in whom the second mutation was a c.1807C-T transition in exon 13, resulting in an arg603-to-ter (R603X; 601460.0013) substitution; a 28-year-old man (patient 17), who presented with CNSU of the jejunum and ileum but also fulfilled the criteria for PHO, in whom the second mutation was a c.547G-A transition in exon 4, resulting in a gly183-to-arg (G183R; 601460.0026) substitution at a highly conserved residue; and a 75-year-old woman (patient 18) with CNSU of the jejunum and ileum, who also exhibited digital clubbing, periostosis, and arthralgias and effusions of the large joints, in whom the second mutation was a c.421G-T transversion in exon 4, resulting in a glu141-to-ter (E141X; 601460.0023) substitution. Functional analysis in transfected HEK293 cells demonstrated that none of the 4 mutants was unable to take up PGE, indicating loss of function as a PGE transporter.
In 2 Korean brothers (family 3) with PHO, Lee et al. (2016) identified homozygosity for the c.940+1G-A mutation (c.940+1G-A, NM_005630.2) in intron 7 of the SLCO2A1 gene, for which their unaffected father was heterozygous. DNA was unavailable from their unaffected mother. The authors noted that family 3 had been independently reported by Kim et al. (2015). Lee et al. (2016) also identified the c.940+1G-A variant in compound heterozygous state in a 19-year-old Korean man (family 2) with PHO, in whom the second mutation was the previously reported R603X substitution (601460.0013). His unaffected parents were each heterozygous for 1 of the mutations. Both brothers from family 3 experienced watery diarrhea, and 1 brother as well as the proband from family 2 had patent ductus arteriosus (PDA) that required surgical repair in infancy. Lee et al. (2016) reviewed published reports of SLCO2A1 mutations in PHO, and noted that the c.940+1G-A variant was recurrent in Japanese and Chinese patients; they suggested that it might be a common mutation in the Korean population as well.
In a review of 46 Japanese patients from 43 families with CNSU and mutation in the SLCO2A1 gene, Umeno et al. (2018) noted that the most frequent mutation was c.940+1G-A, present in 50 (54%) of 92 alleles, and that 17 (37%) of the patients carried the mutation in homozygous state.
In 3 affected brothers from a consanguineous Turkish family with primary hypertrophic osteoarthropathy (PHOAR2; 614441), Seifert et al. (2012) identified homozygosity for a 1-bp insertion (c.830insT, NM_005630.2) in exon 6 of the SLCO2A1 gene, causing a frameshift within the sixth transmembrane domain predicted to result in a premature termination codon. One of the affected brothers was 8 years old and displayed only delayed closure of fontanels, but was considered likely to develop further manifestations upon or after puberty. Both parents and 4 unaffected sibs were heterozygous carriers of the mutation. Reexamination of heterozygous carriers in this family revealed that the father had mild isolated digital clubbing. Seifert et al. (2012) suggested that penetrance of isolated digital clubbing might be influenced by other unknown genetic factors, environmental stimuli, and/or individual lifestyle.
In a 21-year-old Han Chinese man (P19) with pachydermia, digital clubbing, periostosis, and hyperhidrosis, who was also anemic and experienced gastrointestinal hemorrhage (PHOAR2E syndrome; 614441), Li et al. (2017) identified compound heterozygosity for a c.754C-T transition (c.754C-T, NM_005630.2) in exon 6 of the SLCO2A1 gene, resulting in an arg252-to-ter (R252X) substitution, and a c.1106G-A transition in exon 9, resulting in a gly369-to-asp (G369D; 601460.0022) substitution at a highly conserved residue. The G369D variant was present at very low minor allele frequency (0.00007978) in the ExAC database.
Associations Pending Confirmation
In a 28-year-old Dutch man with isolated congenital digital clubbing, Seifert et al. (2012) identified heterozygosity for the R252X substitution in the third extracellular loop of SLCO2A1. The mutation, which was present in his unaffected father, was not found in 150 control chromosomes. Quantitative PCR in both heterozygous individuals demonstrated significant reduction of SLCO2A1 mRNA level compared to control, consistent with nonsense-mediated decay. Seifert et al. (2012) suggested that further factors regulating prostaglandin E2 synthesis, degradation, or signaling might influence the pathogenesis of primary hypertrophic osteoarthropathy (see 167100) or distal clubbing.
In 4 brothers with primary hypertrophic osteoarthropathy (PHOAR2E; 614441) from a consanguineous Hispanic family of Colombian ancestry, Diggle et al. (2012) identified homozygosity for a c.1259G-T transversion (c.1259G-T, NM_005630.2) in exon 9 of the SLCO2A1 gene, resulting in a cys420-to-phe (C420F) substitution at a highly conserved residue in the ninth transmembrane domain. The unaffected parents were each heterozygous for the mutation. Functional analysis in transiently transfected HeLa cells demonstrated that the C420F construct stimulated 10% or less of the uptake of radiolabeled PGE2 that was stimulated by a wildtype construct. A 34-year-old sister who was also homozygous for C420F had no musculoskeletal or skin symptoms, but did have severe transfusion-dependent anemia and mild digital clubbing.
In 2 brothers with primary hypertrophic osteoarthropathy (PHOAR2E; 614441) from a consanguineous North African family, Diggle et al. (2012) identified homozygosity for a c.253A-T transversion (c.253A-T, NM_005630.2) in exon 3 of the SLCO2A1 gene, resulting in an ile85-to-phe (I85F) substitution at a highly conserved residue in the second transmembrane domain. The first-cousin unaffected parents were each heterozygous for the mutation. In addition, there was a 19-year-old asymptomatic sister who was also homozygous for the mutation.
PHOAR2-Enteropathy Syndrome
In an Italian man with primary hypertrophic osteoarthropathy (PHOAR2E; 614441), originally described by Castori et al. (2005), Diggle et al. (2012) identified homozygosity for a c.310G-T transversion (c.310G-T, NM_005630.2) in exon 3 of the SLCO2A1 gene, resulting in a gly104-to-ter (G104X) substitution in the third transmembrane domain.
Autosomal Dominant Primary Hypertrophic Osteoarthropathy
In a 4-generation French Canadian family (family 1867) with autosomal dominant primary hypertrophic osteoarthropathy (PHOAD; 167100) in which digital clubbing was restricted to male members, Guda et al. (2014) identified heterozygosity for the G104X mutation in SLCO2A1 in the proband and his affected father and nephew. The proband also had early-onset colon cancer at age 48 years, and a sessile serrated adenoma was detected in the nephew at age 24 years. Sessile serrated adenomas also arose in 2 sisters of the proband who carried the G104X mutation, at ages 54 and 57 years, respectively. The clubbing phenotype appeared to be incompletely penetrant in males as well as females, since the affected nephew's 26-year-old brother carried the mutation but did not exhibit digital clubbing; he had not been evaluated for colonic neoplasia.
In a 42-year-old Chinese man (family 6) with digital clubbing, furrowing of facial skin, and periosteal overgrowth of the long bones (PHOAD; 167100), who also experienced recurrent watery diarrhea, Zhang et al. (2013) identified heterozygosity for a splicing mutation, c.861+2T-C (NC_000003), in intron 6 of the SLCO2A1 gene. The mutation was inherited from his unaffected father, and was not found in 125 controls.
PHOAR2-Enteropathy Syndrome
In a 24-year-old Chinese man (P34) with pachydermia, digital clubbing, periostosis, and hyperhidrosis (PHOAR2E; 614441), Li et al. (2017) identified compound heterozygosity for the c.861+2T-C splice site mutation in the SLCO2A1 gene, and a c.1095C-A transversion in exon 8, resulting in an asn365-to-lys (N365K; 601460.0033) substitution at a highly conserved residue. The N365K variant was not found in the ExAC database.
In 3 Korean brothers (family 1) with digital clubbing, pachydermia, and periostosis (PHOAD; 167100), Lee et al. (2016) identified heterozygosity for a c.302T-G transversion (c.302T-G, NM_005630.2) in exon 3 of the SLC2A1 gene, resulting in an ile101-to-ser (I101S) substitution. The proband's unaffected son did not carry the mutation; DNA was unavailable from the brothers' unaffected parents for analysis.
PHOAR2-Enteropathy Syndrome
For discussion of the c.1807C-T transition (c.1807C-T, NM_005630) in exon 13 of the SLCO2A1 gene, resulting in an arg603-to-ter (R603X) substitution, that was found in compound heterozygous state in 2 Japanese sisters (patients 4 and 5) with chronic nonspecific ulcers (CNSU) of the stomach, duodenum, and ileum, who also exhibited acne, large joint arthralgias, and hyperhidrosis (PHOAR2E; 614441) by Umeno et al. (2015), see 601460.0004.
Umeno et al. (2015) also reported an 18-year-old Japanese girl (patient 15) with anemia and CNSU of the duodenum and ileum who was compound heterozygous for R603X and a splice site mutation in SLCO2A1 (c.940+1G-A; 601460.0005), and a 59-year-old Japanese woman (patient 10) with CNSU of the ileum who was compound heterozygous for R603X and a c.421G-T transversion in exon 4, resulting in a glu141-to-ter (E141X; 601460.0023) substitution. The latter 2 patients did not exhibit features of PHO. Functional analysis in transfected HEK293 cells demonstrated that none of the mutants was able to take up PGE, indicating loss of function as a PGE transporter.
For discussion of the c.1807C-T transition (c.1807C-T, NM_005630.2) in exon 13 of the SLCO2A1 gene, resulting in an arg603-to-ter (R603X) substitution, that was found in compound heterozygous state in a 19-year-old Korean man (family 2) with primary hypertrophic osteoarthropathy (PHO) by Lee et al. (2016), see 601460.0005.
In 2 Chinese men (P17 and P33) with features of PHO, including digital clubbing and periostosis, Li et al. (2017) identified compound heterozygosity for the R603X substitution and another mutation in the SLCO2A1 gene: in P17, the second mutation was a c.1624C-T transition in exon 11, resulting in an arg542-to-cys (R542C; 601460.0024) substitution at a highly conserved residue; and in P33, the second mutation was a c.1106-1G-A transition in intron 8 (601460.0025). The R542C variant was present at very low minor allele frequency (0.0002221) in the ExAC database. Neither man was reported to have gastrointestinal symptoms.
In a review of 46 Japanese patients from 43 families with CNSU and mutation in the SLCO2A1 gene, Umeno et al. (2018) noted that the R603X variant was present in 20 (22%) of 92 alleles, making it the second most frequent mutation identified.
In a Chinese man (family 12) with PHO, Xu et al. (2021) identified homozygosity for the R603X substitution. His heterozygous father exhibited only pachydermia and periostosis, whereas his heterozygous mother was clinically unaffected. The proband in family 12 had been previously studied by Li et al. (2017) as P15, and was reported to have gastrointestinal hemorrhage and anemia.
Autosomal Dominant Primary Hypertrophic Osteoarthropathy
In affected individuals from 2 Chinese families (6 and 7) segregating autosomal dominant PHO (PHOAD; 167100), Xu et al. (2021) identified heterozygosity for the R603X substitution (c.1807C-T, NM_005630.2) in the SLCO2A1 gene, which was not found in 250 Chinese controls. In family 6, the male proband had complete PHO, with pachydermia, digital clubbing, periostosis, and joint swelling, as well as gastrointestinal abnormalities, whereas his sister and mother, who also carried the R603X variant, exhibited only pachydermia. In family 7, the male proband and his maternal uncle had digital clubbing and periostosis, whereas the proband's mother had only periostosis.
For discussion of the c.621C-A transversion (c.621C-A, NM_005630.2) in exon 4 of the SLCO2A1 gene, resulting in a tyr207-to-ter (Y207X) substitution, that was reported in compound heterozygous state in a male Chinese proband (family 8) with autosomal recessive primary hypertrophic osteoarthropathy-enteropathy syndrome (PHOAR2E; 614441) by Xu et al. (2021), see 601460.0004.
In 5 members of a 3-generation Chinese family (family 1) segregating autosomal dominant primary hypertrophic osteoarthropathy (PHOAD; 167100), Xu et al. (2021) identified heterozygosity for a c.1660G-A transition (c.1660G-A, NM_005630.2) in exon 12 of the SLCO2A1 gene, resulting in a gly554-to-arg (G554R) substitution. The mutation was not found in 250 Chinese controls. The proband was previously studied as P28 by Li et al. (2017) and reported to have watery diarrhea, gastrointestinal hemorrhage, and anemia. Other heterozygous carriers of the G554R variant included the proband's son, maternal uncle, and cousin, who all exhibited only digital clubbing, and his mother, who was clinically and radiologically unaffected.
PHOAR2-Enteropathy Syndrome
Xu et al. (2021) reported 2 Chinese brothers with PHO (family 11) who were compound heterozygous for the G554R mutation and a splicing mutation (c.1814+1G-A; 601460.0016) in intron 13 of the SLCO2A1 gene. The mutation was not found in 250 Chinese controls. The proband had pachydermia, digital clubbing, periostosis, and joint swelling, as well as gastrointestinal abnormalities, whereas his brother had only digital clubbing and periostosis. Their father, who was heterozygous for the G554R variant, showed only periostosis, whereas their mother, who was heterozygous for the splicing variant, was clinically unaffected.
For discussion of the c.1814+1G-A transition (c.1814+1G-A, NM_005630.2) in intron 13 of the SLCO2A1 gene, that was found in compound heterozygous state in a male Chinese proband (family 11) with autosomal recessive primary hypertrophic osteoarthropathy-enteropathy syndrome (PHOAR2E; 614441) by Xu et al. (2021), see 601460.0015.
For discussion of the c.1668G-C transversion in exon 12 of the SLCO2A1 gene, resulting in a gln556-to-his (Q556H) substitution, that was found in compound heterozygous state in a 53-year-old Japanese man (family 3) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Busch et al. (2012), see 601460.0005.
In 2 Indian brothers (family 2) with typical features of primary hypertrophic osteoarthropathy (PHO), including digital clubbing, hyperhidrosis, and large joint swelling (PHOAR2E; 614441), Busch et al. (2012) identified homozygosity for a c.763G-A transition in exon 6 of the SLCO2A1 gene, resulting in a gly255-to-arg (G255R) substitution at a highly conserved residue. The presence or absence of gastrointestinal symptoms in the affected brothers was not reported.
In a Chinese male proband and 2 affected sisters (family 1) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441), Zhang et al. (2013) identified homozygosity for a 1-bp deletion (c.855delA) in the SLCO2A1 gene, causing a frameshift predicted to result in a premature termination codon (Ala286GlnfsTer35). The male proband exhibited pachydermia, digital clubbing, and diaphyseal periostosis, features of primary hypertrophic osteoarthropathy (PHO) that were not present in his affected sisters. All 3 sibs had severe anemia and hypoalbuminemia, and all 3 experienced recurrent watery diarrhea that was said to be triggered by cold drinks, but no overt gastrointestinal hemorrhage.
In a 57-year-old Japanese woman (family A) who developed anemia at age 17 years and was diagnosed with chronic nonspecific ulcers of the ileum at age 43, who also had digital clubbing (PHOAR2E; 614441), Umeno et al. (2015) identified homozygosity for a splice site mutation (c.1461+1G-C, NM_005630) in intron 10 of the SLCO2A1 gene. Her unaffected parents, sibs, and 2 unaffected children were all heterozygous for the mutation, which was not found in 747 Japanese controls. Sequencing of RT-PCR products of patient transcripts revealed that the mutation led to a 23-bp frameshift insertion into intron 10, resulting in premature termination (Ile488LeufsTer11).
In a 72-year-old Japanese woman (patient 9) who had onset of anemia and hypoproteinemia at age 40 years and was diagnosed with chronic nonspecific multiple ulcers of the ileum at age 66, who also exhibited clubbing of the fingers and periostosis (PHOAR2E; 614441), Umeno et al. (2015) identified homozygosity for a c.1372G-T transversion (c.1372G-T, NM_005630) in exon 10 of the SLCO2A1 gene, resulting in a val458-to-phe (V458F) substitution. Functional analysis in transfected HEK293 cells demonstrated that the V458F mutant was unable take up PGE, indicating loss of function as a PGE transporter.
In a 25-year-old Han Chinese man (P26) with pachydermia, digital clubbing, periostosis, and hyperhidrosis, Li et al. (2017) identified homozygosity for the V458F substitution, which occurred at a highly conserved residue and was not found in the ExAC database. The patient was not reported to have had watery diarrhea, gastrointestinal hemorrhage, or anemia; the presence or absence of gastrointestinal ulcers was not sought in this study.
In a 23-year-old Chinese man (family 2) with pachydermia, digital clubbing, periostosis, hyperhidrosis, and watery diarrhea (PHOAR2E; 614441), Zhang et al. (2013) identified homozygosity for a c.1106G-A transition in exon 9 of the SLCO2A1 gene, resulting in a gly369-to-asp (G369D) substitution. His unaffected first-cousin parents were heterozygous for the mutation, as were his unaffected grandmothers and an unaffected sister; 2 other unaffected sibs did not carry the mutation.
In a 19-year-old Chinese man (P27) with pachydermia, digital clubbing, periostosis, and hyperhidrosis, Li et al. (2017) identified compound heterozygosity for the G369D substitution (c.1106G-A, NM_005630.2) and a c.289C-T transition in exon 3 of the SLCO2A1 gene, resulting in an arg97-to-cys (R97C; 601460.0032) substitution. Both substitutions occurred at highly conserved residues, and both variants were found at very low minor allele frequency (0.00007978; 0.00002575) in the ExAC database. In a 21-year-old Chinese man (P19) with pachydermia, digital clubbing, periostosis, and hyperhidrosis, who was also anemic and experienced gastrointestinal hemorrhage, the authors identified compound heterozygosity for G369D and a previously reported nonsense mutation in SLCO2A1 (R252X; 601460.0007).
For discussion of the c.421G-T transversion (c.421G-T, NM_005630) in exon 4 of the SLCO2A1 gene, resulting in a glu141-to-ter (E141X) substitution, that was found in compound heterozygous state in a 75-year-old Japanese woman (patient 18) with chronic nonspecific ulcers (CNSU) of the jejunum and ileum, who also exhibited digital clubbing, periostosis, and arthralgias and effusions of the large joints (PHOAR2E; 614441) by Umeno et al. (2015), see 601460.0005. The authors also reported a 59-year-old Japanese woman (patient 10) with CNSU of the ileum, who did not exhibit features of PHO, who was compound heterozygous for E141X and another nonsense mutation in the SLCO2A1 gene (R603X; 601460.0013).
For discussion of the c.1624C-T transition (c.1624C-T, NM_005630.2) in exon 11 of the SLCO2A1 gene, resulting in an arg542-to-cys (R542C) substitution at a highly conserved residue, that was found in compound heterozygous state in 2 Chinese men (P17 and P05) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Li et al. (2017), see 601460.0013 and 601460.0030, respectively.
For discussion of the splice site mutation (c.1106-1G-A, NM_005630.2) in intron 8 of the SLCO2A1 gene that was found in compound heterozygous state in a 25-year-old Chinese man (P33) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Li et al. (2017), see 601460.0013.
For discussion of the c.547G-A transition (c.547G-A, NM_005630) in exon 4 of the SLCO2A1 gene, that was found in compound heterozygous state in a 28-year-old Japanese man (patient 17) who presented with chronic nonspecific ulcers (CNSU) of the jejunum and ileum, but who also fulfilled the criteria for primary hypertrophic osteoarthropathy (PHOAR2E; 614441) by Umeno et al. (2015), see 601460.0005.
In a 19-year-old Chinese man (P08) with pachydermia, digital clubbing, periostosis, hyperhidrosis, and watery diarrhea, Li et al. (2017) identified compound heterozygosity for the G183R substitution and another missense mutation in the SLCO2A1 gene: a c.178G-A transition in exon 2, resulting in a glu60-to-lys (E60K; 601460.0027) substitution. Both mutations occurred at highly conserved residues; the E60K variant was not found in the ExAC database, whereas the G183R substitution was present at very low minor allele frequency (0.0000412).
In a 39-year-old Mexican man (patient 1) with recurrent ulceration of the duodenum and erythematous gastropathy complicated by upper gastrointestinal bleeding, who also exhibited digital clubbing, palmoplantar hyperhidrosis, and cutis verticis gyrata, Kimball et al. (2024) identified homozygosity for the G183R mutation in the SLCO2A1 gene. The proband had a sister who died at age 15 years due to gastointestinal complications; her mutation status was not reported.
For discussion of the c.178G-A transition (c.178G-A, NM_005630.2) in exon 2 of the SLCO2A1 gene, resulting in a glu60-to-lys (E60K) substitution, that was found in compound heterozygous state in 3 unrelated Chinese men with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Li et al. (2017), see 601460.0015, 601460.0026, and 601460.0028, respectively.
In a 24-year-old Chinese man (P24) with pachydermia, digital clubbing, periostosis, and watery diarrhea (PHOAR2E; 614441), Li et al. (2017) identified compound heterozygosity for a c.310G-A transition (c.310G-A, NM_005630.2) in exon 3 of the SLCO2A1 gene, resulting in a gly104-to-arg (G104R) substitution, and a c.178G-A transition in exon 2, resulting in a glu60-to-lys (E60K; 601460.0027) substitution. Both mutations occurred at highly conserved residues; the E60K variant was not found in the ExAC database, whereas the G104R substitution was present at very low minor allele frequency (0.00002526).
For discussion of the c.759G-A transition (c.759G-A, NM_005630.2) in exon 6 of the SLCO2A1 gene, resulting in a trp253-to-ter (W253X) substitution, that was found in compound heterozygous state in a 24-year-old Chinese man (P11) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Li et al. (2017), see 601460.0002.
In a 26-year-old Chinese man (P18) with pachydermia, digital clubbing, periostosis, hyperhidrosis, and anemia (PHOAR2E; 614441), Li et al. (2017) identified homozygosity for a c.440G-A transition (c.440G-A, NM_005630.2) in exon 4 of the SLCO2A1 gene, resulting in a trp147-to-ter (W147X) substitution. The W147X variant was also found in compound heterozygosity in a 36-year-old Chinese man (P05) with digital clubbing, periostosis, and joint swelling, whose second mutation was a c.1624C-T transition in exon 11, resulting in an arg542-to-cys (R542C; 601460.0024) substitution; and in a 22-year-old Chinese man (P36) with pachydermia, digital clubbing, periostosis, hyperhidrosis, and anemia, whose second mutation was a c.1370C-T transition in exon 10, resulting in a pro457-to-leu (P457L; 601460.0031) substitution. The R542C and P457L substitutions occurred at highly conserved residues, and both were present at very low minor allele frequency (0.0002221; 0.00004123) in the ExAC database.
For discussion of the c.1370C-T transition (c.1370C-T, NM_005630.2) in exon 10 of the SLCO2A1 gene, resulting in a pro457-to-leu (P457L) substitution, that was found in compound heterozygous state in a 22-year-old Chinese man (P36) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Li et al. (2017), see 601460.0030.
For discussion of the c.289C-T transition (c.289C-T, NM_005630.2) in exon 3 of the SLCO2A1 gene, resulting in an arg97-to-cys (R97C) substitution, that was found in compound heterozygous state in a 19-year-old Chinese man (P27) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Li et al. (2017), see 601460.0022.
For discussion of the c.1095C-A transversion (c.1095C-A, NM_005630.2) in exon 8 of the SLCO2A1 gene, resulting in an asn365-to-lys (N365K) substitution, that was found in compound heterozygous state in a 24-year-old Chinese man (P34) with PHOAR2-enteropathy syndrome (PHOAR2E; 614441) by Li et al. (2017), see 601460.0011.
In a 24-year-old Mexican man (patient 2) with primary hypertrophic osteoarthropathy and anemia with congestive gastropathy (PHOAR2E; 614441), Kimball et al. (2024) identified homozygosity for a 1-bp deletion in exon 13 of the SLCO2A1 gene (c.1768del), causing a frameshift predicted to result in a premature termination codon (Arg590GlyfsTer39). The variant was present at very low minor allele frequency (0.00132) in the gnomAD database.
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