Solute Carrier Organic Anion Transporter Family, Member 2A1 Gene Research Articles

Atypical primary hypertrophic osteoarthropathy diagnosed with a novel SLCO2A1 gene mutation

AbstractPrimary hypertrophic osteoarthropathy (HOA) is a rare condition with no identifiable cause, accounting for 3%–5% of all HOA cases. It is challenging to identify incomplete primary HOA, which can be misdiagnosed as other hypertrophic periostitis diseases. At least two of the four criteria set by Borochowitz and Rimoin (1990) must be present to diagnose primary HOA. Diagnostic difficulties due to incomplete or atypical manifestations are common. We present a case of incomplete primary PHOA at Hanoi Medical University Hospital in Vietnam. A 37-year-old male presented with ankle joint pain for nearly four years. X-ray and magnetic resonance imaging showed periostitis in the tibias and fibulas, which could not exclude Camurati–Engelmann disease. Finally, gene sequencing on the Illumina MiSeq system identified a missense mutation (c.295C>T) in the solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene on chromosome 3. Our case report and literature review aim to improve specialists' understanding of incomplete primary HOA and reduce the frequency of missed diagnoses.

Touraine-Solente-Gole syndrome: pathogenic variant in SLCO2A1 presented with polyarthralgia and digital clubbing

BackgroundPrimary Hypertrophic Osteoarthropathy (PHO), also known as Touraine-Solente-Gole Syndrome, is a rare, multisystemic autosomal recessive disorder caused by pathogenic variants in the 15-hydroxyprostaglandin dehydrogenase (HPGD) or Solute Carrier Organic Anion Transporter Family Member 2A1 (SLCO2A1) genes. However, autosomal dominant transmission has also been described in some families with incomplete penetrance. PHO usually starts in childhood or adolescence, presenting with digital clubbing, osteoarthropathy, and pachydermia. We described a complete form of the syndrome in a male patient with a homozygous variant in the SLCO2A1 gene (c.1259G > T).Case presentationA 20-year-old male was referred to our Pediatric Rheumatology Clinic with a five-year history of painful and swollen hands, knees, ankles and feet, prolonged morning stiffness and relief with non-steroidal antiinflammatory drugs. He also reported late onset facial acne and palmoplantar hyperhidrosis. Family history was irrelevant and parents were non-consanguineous. On clinical examination, he presented clubbing of the fingers and toes, moderate acne and marked facial skin thickening with prominent scalp folds. He had hand, knee, ankles and feet swelling. Laboratory investigations showed elevated inflammatory markers. Complete blood count, renal and hepatic function, bone biochemistry were normal, as well as immunological panel. Plain radiographs revealed soft tissue swelling, periosteal ossification and cortical thickening of the skull, phalanges, femur and toe acroosteolysis. Due to the absence of other clinical signs suggesting a secondary cause, we suspected PHO. A genetic study revealed a likely pathogenic variant, c.1259G > T(p.Cys420Phe), in homozygosity in the SLCO2A1 gene, thus confirming the diagnosis. The patient started oral naproxen with significant clinical improvement.ConclusionsPHO should be kept in the differential diagnosis of inflammatory arthritis affecting children, often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). To the best of our knowledge, this is the second genetically confirmed case of PHO in a Portuguese patient (first variant c.644 C > T), both made at our department.

A Complete Form of Pachydermoperiostosis Accompanied by a Pituitary Microadenoma

Pachydermoperiostosis is a rare genetic disease that is associated with HPGD (15-hydroxyprostaglandin dehydrogenase) and SLCO2A1 (solute carrier organic anion transporter family member 2A1) gene mutations. It is characterized by three major phenotypes, namely, pachydermia, periostosis, and digital clubbing. Clinically, misdiagnoses such as acromegaly and thyroid acropachy are commonly confused with pachydermoperiostosis. Integral medical history, physical examination, endocrinological tests, and multiple disciplinary cooperation are extremely significant in the accurate diagnosis of pachydermoperiostosis. The co-existence of pachydermoperiostosis and pituitary adenoma is rarely recorded and discussed. In this case, we present a young male patient with a complete form of pachydermoperiostosis and a nonfunctional pituitary microadenoma, which has rarely been reported.

Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial

BackgroundPrimary hypertrophic osteoarthropathy (PHO) is a rare disease involving joint, bone and skin. Two underlying genes responsible for this disease—hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1)—are both associated with aberrant accumulation of prostaglandin E2 (PGE2). Cyclooxygenase-2 (COX-2) is a key enzyme in PGE2 synthesis. This study was intended to evaluate the safety and efficacy of COX-2 inhibitor in the treatment of PHO. MethodsWe recruited patients presenting to Peking Union Medical Hospital between January 2009 and December 2016 who were diagnosed with PHO. Participants were given the COX-2 inhibitor etoricoxib (60 mg once daily) and followed up for 9 months. Gene analysis was performed at baseline. The following data were collected at baseline and during treatment: visual analogue score (VAS), volume of the distal middle finger (VDMF), knee joint circumference (KJC), serum and urinary levels of prostaglandin E2 (PGE2) and PGE metabolite (PGE-M) and serum levels of inflammatory markers. ResultsA total of 27 patients were recruited, including seven patients with PHO type I (PHOAR1) carrying HPGD gene mutations and 20 patients with PHO type II (PHOAR2) carrying SLCO2A1 gene mutations. After treatment with etoricoxib, the majority of patients experienced resolution of symptoms including pachydermia (60.9%), joint swelling (100%), digital clubbing (74.1%) and hyperhidrosis (55.0%). In both the PHO subtypes, serum and urinary levels of PGE2 were elevated at baseline and declined sharply upon treatment. For PHOAR1 patients, serum and urinary PGE-M levels were relatively low and demonstrated minimal response to COX-2 inhibition. Among PHOAR2 patients, mean serum and urinary levels of PGE-M presented at a high level at baseline and were normalized after 3 months of treatment. No severe adverse effects were reported during the study period. ConclusionsWe found COX-2 inhibitor to be safe and effective for the treatment of PHO in our cohort. The translational potential of this articleThe underlying genes responsible for PHO suggest COX inhibitor as potential therapy, and our study demonstrates the efficacy and safety of this treatment.

Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study

Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis, and pachydermia. Based on two causative genes, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1), PHO is categorized into two subtypes: hypertrophic osteoarthropathy, primary, autosomal recessive 1 (PHOAR1) and hypertrophic osteoarthropathy, primary, autosomal recessive 2 (PHOAR2). In this study, we summarized the clinical manifestations and analyzed SLCO2A1 gene in 23 PHOAR2 patients in our center. As a result, 18 patients displayed complete phenotypes of PHO with digital clubbing, periostosis, and pachydermia. 29 mutations were found in total, and 22 of them were novel mutations including 13 missense, three nonsense, four deletion, one frame-shift and one splicing site mutations. Compared with nine PHOAR1 patients we previously reported, PHO patients with SLCO2A1 mutations were all male and presented with a later onset age. Peptic ulcers and myelofibrosis occurred only in PHOAR2 patients. The urinary level of prostaglandin E2 metabolite (PGEM) is significantly higher in PHOAR2 patients than that in PHOAR1 group. In conclusion, this study was the largest cohort to date to summarize PHOAR2 patients and to assess the phenotypic difference between two subtypes of PHO. The difference of urinary PGEM concentration between two subtypes is helpful for the differential diagnosis of PHO.

Pachydermoperiostosis of the complete type: A novel missense mutation c.101T > C in the SLCO2A1 gene

We report on a rare case of pachydermoperiostosis (PDP) in a 25-year-old male who was admitted to our hospital because of enlargement of fingers and toes. Through examination, we found some typical features on the patient including finger clubbing, periostosis, pachydermia, and cutis verticis gyrata (CVG). But laboratory tests were almost within normal ranges, which ruled out rheumatic arthritis, osteopulmonary arthropathy, thyroid acropathy, and acromegaly. Then, we diagnosed this case as PDP, which was confirmed by gene sequencing. The pathogenesis is concerned with abnormal rise of the level of PGE2 that results from the solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene defect. Meanwhile, we found a novel missense mutation c.101T > C of the SLCO2A1 gene in the patient with PDP.

Pediatric-onset Chronic Nonspecific Multiple Ulcers of Small Intestine: A Nationwide Survey and Genetic Study in Japan.

We performed a Japanese nationwide survey of pediatric-onset chronic nonspecific multiple ulcers of the small intestine between January 2000 and July 2013 in 176 institutions of pediatric surgery or pediatric gastroenterology and clarified the clinical features associated with genetic abnormalities in the Solute Carrier Organic Anion Transporter Family, Member 2A1 (SLCO2A1) gene. A total of 4 cases (3 girls and 1 boy) were diagnosed in this series, which had to be differentiated from Crohn disease, Behçet disease, tuberculosis, or drug-induced enteropathy. Clinical symptoms appeared in infants and accurate diagnosis required several years. Medical therapies for inflammatory bowel disease were administered in all patients; however, 2 of the 4 patients had mutation in the SLCO2A1 gene which are responsible for primary hypertrophic osteoarthopathy, and underwent strictureplasty or ileal resection after long-term follow-up. Pediatric gastroenterologists should include this new entity in the differential diagnosis of small intestinal ulcers and inflammatory bowel disease.

291 Mutations in DNA Polymerase Genes (POLD1 & POLE) in Individuals Having Early-Onset Colorectal Cancer and/or Multiple Adenomas

Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality through the endoscopic detection and removal of colorectal adenomas. Still, these patients are at increased risk for developing metachronous adenomas or even cancer, with the recurrence rate reaching the 50%. The pleiotropic effects of higher levels of PGE2 contribute to key steps of cancer development, including cell proliferation, angiogenesis, invasiveness and migration, inhibition of apoptosis and immunosurveillance as a refletion of deregulation of ATP-binding cassete sub-family c member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) genes responsable for carrying PGE2 accross the membrane. To evaluate the influence of genetic polymorphisms in ABCC4 and SLCO2A1 on the risk and time for colorectal adenoma recurrence a retrospective case-cohort study was designed gathering 195 patients diagnosed with colorectal adenomas. Adenoma reccurence was defined has the diagnosis of an adenoma after a total normal colonoscopy at least one year after the initial diagnosis. Thirty-three tagSNPs were characterized using the MassARRAY iPLEX Gold technology based on multiplex amplification followed by mass-spectrometric product separation. Three tagSNPs were identified as susceptibility biomarkers for colorectal adenoma recurrence after a bootstrap analysis. The rs1131598GG homozygous genotype of SLCO2A1 gene was associated with an enhanced risk of 6.3 (95%CI:1.31-30.0, P=0.021). In contrast and under a dominant model of inheritance, the rs1751031 and rs9524821 polymorphisms in ABCC4 gene displayed a protective behaviour (OR=0.29, 95%CI:0.12-0.72, P=0.007 and OR=0.42, 95%CI:0.19-0.93, P=0.033, respectively). Furthermore, when stratifying patients considering the endoscopic findings at baseline colonoscopy, low-risk individuals carriers of rs2274403AA genotype in ABCC4 gene had a lower interval until recurrence (85 (29140) vs 122 (109-135), P=0.011) with 44% of metachronous tumors developing by 36 months (vs 23% for AG/GG). This study demonstrates for the first time the involvement of genetic variants in PGE2 transporters in colorectal adenoma recurrence. The incorporation of genetically-based approaches might allow an optimization of current risk models for the development of metachronous colorectal adenomas or even more advanced lesions possible laeding to a decrease in CRC burden and mortality.

289 Genetic Variability in SLCO2A1 and ABCC4 Genes Encoding for Prostaglandin E2 Transporters Modulate the Susceptibility for Colorectal Adenomas Recurrence After Polypectomy: An Opportunity for Individualized Surveillance?

Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality through the endoscopic detection and removal of colorectal adenomas. Still, these patients are at increased risk for developing metachronous adenomas or even cancer, with the recurrence rate reaching the 50%. The pleiotropic effects of higher levels of PGE2 contribute to key steps of cancer development, including cell proliferation, angiogenesis, invasiveness and migration, inhibition of apoptosis and immunosurveillance as a refletion of deregulation of ATP-binding cassete sub-family c member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) genes responsable for carrying PGE2 accross the membrane. To evaluate the influence of genetic polymorphisms in ABCC4 and SLCO2A1 on the risk and time for colorectal adenoma recurrence a retrospective case-cohort study was designed gathering 195 patients diagnosed with colorectal adenomas. Adenoma reccurence was defined has the diagnosis of an adenoma after a total normal colonoscopy at least one year after the initial diagnosis. Thirty-three tagSNPs were characterized using the MassARRAY iPLEX Gold technology based on multiplex amplification followed by mass-spectrometric product separation. Three tagSNPs were identified as susceptibility biomarkers for colorectal adenoma recurrence after a bootstrap analysis. The rs1131598GG homozygous genotype of SLCO2A1 gene was associated with an enhanced risk of 6.3 (95%CI:1.31-30.0, P=0.021). In contrast and under a dominant model of inheritance, the rs1751031 and rs9524821 polymorphisms in ABCC4 gene displayed a protective behaviour (OR=0.29, 95%CI:0.12-0.72, P=0.007 and OR=0.42, 95%CI:0.19-0.93, P=0.033, respectively). Furthermore, when stratifying patients considering the endoscopic findings at baseline colonoscopy, low-risk individuals carriers of rs2274403AA genotype in ABCC4 gene had a lower interval until recurrence (85 (29140) vs 122 (109-135), P=0.011) with 44% of metachronous tumors developing by 36 months (vs 23% for AG/GG). This study demonstrates for the first time the involvement of genetic variants in PGE2 transporters in colorectal adenoma recurrence. The incorporation of genetically-based approaches might allow an optimization of current risk models for the development of metachronous colorectal adenomas or even more advanced lesions possible laeding to a decrease in CRC burden and mortality.

290 Relevance of DNA Repair Polymorphisms As Genetic Markers of Gastric Cancer Susceptibility and Prognosis in Caucasians

Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality through the endoscopic detection and removal of colorectal adenomas. Still, these patients are at increased risk for developing metachronous adenomas or even cancer, with the recurrence rate reaching the 50%. The pleiotropic effects of higher levels of PGE2 contribute to key steps of cancer development, including cell proliferation, angiogenesis, invasiveness and migration, inhibition of apoptosis and immunosurveillance as a refletion of deregulation of ATP-binding cassete sub-family c member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) genes responsable for carrying PGE2 accross the membrane. To evaluate the influence of genetic polymorphisms in ABCC4 and SLCO2A1 on the risk and time for colorectal adenoma recurrence a retrospective case-cohort study was designed gathering 195 patients diagnosed with colorectal adenomas. Adenoma reccurence was defined has the diagnosis of an adenoma after a total normal colonoscopy at least one year after the initial diagnosis. Thirty-three tagSNPs were characterized using the MassARRAY iPLEX Gold technology based on multiplex amplification followed by mass-spectrometric product separation. Three tagSNPs were identified as susceptibility biomarkers for colorectal adenoma recurrence after a bootstrap analysis. The rs1131598GG homozygous genotype of SLCO2A1 gene was associated with an enhanced risk of 6.3 (95%CI:1.31-30.0, P=0.021). In contrast and under a dominant model of inheritance, the rs1751031 and rs9524821 polymorphisms in ABCC4 gene displayed a protective behaviour (OR=0.29, 95%CI:0.12-0.72, P=0.007 and OR=0.42, 95%CI:0.19-0.93, P=0.033, respectively). Furthermore, when stratifying patients considering the endoscopic findings at baseline colonoscopy, low-risk individuals carriers of rs2274403AA genotype in ABCC4 gene had a lower interval until recurrence (85 (29140) vs 122 (109-135), P=0.011) with 44% of metachronous tumors developing by 36 months (vs 23% for AG/GG). This study demonstrates for the first time the involvement of genetic variants in PGE2 transporters in colorectal adenoma recurrence. The incorporation of genetically-based approaches might allow an optimization of current risk models for the development of metachronous colorectal adenomas or even more advanced lesions possible laeding to a decrease in CRC burden and mortality.

Two novel mutations in the SLCO2A1 gene in a Chinese patient with primary hypertrophic osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO) is a rare monogenetic disease characterized by digital clubbing, periostosis and pachydermia. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been shown to be associated with PHO. Here, we described clinical characteristics in a Chinese patient with PHO, and identified two novel mutations in SLCO2A1: a heterozygous guanine-to-thymidine transition at the invariant −1 position of the acceptor site of intron 2 (c.235-1G>T) and a heterozygous missense mutation p.Pro219Leu (c.656C>T) in exon 5.

Three novel mutations in the SLCO2A1 gene in two Chinese families with primary hypertrophic osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO (MIM 167100)) is a rare genetic disease characterized by pachyderma, periostosis and digital clubbing. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been demonstrated to be pathogenic causes. We aimed to identify the genetic cause of 2 unrelated patients with PHO. Urinary levels of prostaglandin E2 and prostaglandin E metabolite were measured in Proband 1 and his sister by competitive ELISAs. Mutation analysis of the HPGD and SLCO2A1 genes were conducted on both probands with PHO. Genomic DNAs of 100 healthy controls were isolated and subjected to polymerase chain reaction and direct DNA sequencing. The identified mutations were further confirmed in the parents of Proband 1. Protein modeling and data from PolyPhen-2 were used to evaluate the effects of novel missense mutations on protein SLCO2A1. The urinary levels of prostaglandin E2 and prostaglandin E metabolite in Proband 1 were much higher than those in unaffected individuals. Molecular genetic analysis revealed four SLCO2A1 mutations, including 3 novel ones (p.Arg603X, p.Gly183Arg and p.Asn534Lys) and a founder mutation, c.940+1G>A, in two probands with PHO. Missense mutations p.Gly183Arg and p.Asn534Lys, at highly conserved positions, were both predicted to be damaging. Protein modeling indicated that the mutation p.Gly183Arg altered the 3-dimensional structure of SLCO2A1. Three novel mutations within the SLCO2A1 gene have been demonstrated to be associated with Chinese PHO patients.

Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype–genotype correlation in Japanese patients with pachydermoperiostosis

Pachydermoperiostosis (PDP) is a rare genetic disorder characterized by 3 major symptoms: pachydermia including cutis verticis gyrata (CVG), periostosis, and finger clubbing. Recently, a homozygous mutation in the gene HPGD, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), was found to be associated with PDP. However, mutations in HPGD have not been identified in Japanese PDP patients. We aimed to identify a novel responsible gene for PDP using whole exome sequencing by next-generation DNA sequencer (NGS). Five patients, including 2 patient-parent trios were enrolled in this study. Entire coding regions were sequenced by NGS to identify candidate mutations associated with PDP. The candidate mutations were subsequently sequenced using the Sanger method. To determine clinical characteristics, we analyzed histological samples, as well as serum and urinary prostaglandin E2 (PGE2) levels for each of the 5 PDP patients, and 1 additional patient with idiopathic CVG. From initial analyses of whole exome sequencing data, we identified mutations in the solute carrier organic anion transporter family, member 2A1 (SLCO2A1) gene, encoding prostaglandin transporter, in 3 of the PDP patients. Follow-up Sanger sequencing showed 5 different SLCO2A1 mutations (c.940+1G>A, p.E427_P430del, p.G104*, p.T347I, p.Q556H) in 4 unrelated PDP patients. In addition, the splice-site mutation c.940+1G>A identified in 3 of 4 PDP patients was determined to be a founder mutation in the Japanese population. Furthermore, it is likely that the combination of these SLCO2A1 mutations in PDP patients is also associated with disease severity. We found that SLCO2A1 is a novel gene responsible for PDP. Although the SLCO2A1 gene is only the second gene discovered to be associated with PDP, it is likely to be a major cause of PDP in the Japanese population.