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Primary hypertrophic osteoarthropathy, autosomal recessive 2 (PHOAR2) is characterized by digital clubbing, periostosis, and pachydermia resulting from impaired degradation of prostaglandin E2 (PGE2). SLCO2A1 (HGNC:10955) encodes a prostaglandin transporter (PGT) essential for cellular uptake and clearance of PGE2. Biallelic SLCO2A1 variants lead to elevated urinary PGE2 metabolite (PGEM) levels and progressive osteoarthropathy. The ClinGen clinical validity for SLCO2A1–PHOAR2 is classified as Strong based on >25 unrelated probands ([PMID:28963081]), segregation in multiple families, and concordant functional studies. Inheritance is autosomal recessive. The consistent triad of periostosis, clubbing, and pachydermia defines the core phenotype across diverse populations.
Genetic evidence includes a Chinese family with compound heterozygous missense variants c.850A>G (p.Ile284Val) and c.1375T>C (p.Cys459Arg) segregating in two affected siblings ([PMID:31004291]). A single-center cohort of 23 PHOAR2 patients identified 29 SLCO2A1 mutations: 13 missense, three nonsense, four deletions, one frameshift, and one splice-site change in 18 individuals with full PHO phenotype ([PMID:28963081]). Whole-exome sequencing in consanguineous and non-consanguineous pedigrees confirmed homozygous and compound heterozygous mutations in three additional probands ([PMID:22197487]). Over 25 unrelated individuals harbor biallelic SLCO2A1 variants with absence of heterozygous phenotype, supporting recessive inheritance.
The variant spectrum spans missense substitutions (e.g., c.1624C>T (p.Arg542Cys)), splice-site alleles (c.97-1G>A), truncating mutations (c.1634del (p.Asn545fsTer?)), and a recurrent founder splice-site mutation c.940+1G>A in Japanese patients. Loss-of-function mechanisms predominate, with no definitive hypomorphic or deep-intronic variants linked to PHOAR2. Allelic heterogeneity underscores the need for comprehensive sequencing of coding and splice junction regions.
Functional assessment shows that SLCO2A1 loss-of-function variants abolish PGE2 transport in Xenopus oocyte and mammalian cell models, leading to reduced cellular uptake and elevated urinary PGEM ([PMID:22197487], [PMID:23509104]). Immunohistochemistry confirms absent PGT expression at the plasma membrane in affected tissues. These data establish a haploinsufficiency mechanism requiring biallelic disruption. Concordant functional assays and clinical biochemistry demonstrate mechanistic consistency.
Therapeutically, COX-2 inhibition with etoricoxib rapidly normalized serum potassium and reduced PGE2/PGEM levels in PHOAR2 patients presenting with Bartter-like hypokalemia ([PMID:31004291]). Urinary PGEM elevation also distinguishes PHOAR2 from HPGD-related PHOAR1, guiding differential diagnosis. Recognition of gastrointestinal complications, including peptic ulcers and myelofibrosis, informs comprehensive management. Early SLCO2A1 genotyping enables targeted therapy and genetic counseling.
In conclusion, robust genetic and experimental evidence meets ClinGen criteria for a Strong gene–disease association for biallelic SLCO2A1 mutations in PHOAR2. Autosomal recessive inheritance and diverse loss-of-function alleles underlie the phenotype, with functional validation across multiple models. Further studies may refine genotype–phenotype correlations and optimize treatment. Key Take-home: SLCO2A1 sequencing is clinically actionable for diagnosis and management of primary hypertrophic osteoarthropathy type 2.
Gene–Disease AssociationStrong
Genetic EvidenceStrong25 probands with biallelic SLCO2A1 variants, 1 additional affected relative segregating variants, diverse variant classes; reached ClinGen genetic cap Functional EvidenceModerateIn vitro assays demonstrate loss of prostaglandin E2 uptake by SLCO2A1 mutants, supporting loss-of-function mechanism |