BMPR1A – Juvenile Polyposis Syndrome

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by multiple hamartomatous polyps throughout the gastrointestinal tract and a significantly increased risk of colorectal cancer. Germline variants in BMPR1A account for approximately 20%–25% of JPS cases, with SMAD4 variants explaining most of the remainder. BMPR1A encodes a type I serine/threonine kinase receptor in the TGF-β/BMP signaling pathway, critical for colonic epithelial homeostasis.

Genetic evidence for BMPR1A–JPS association includes germline LoF mutations in 10 unrelated probands ([PMID:11381269]) and a cohort study of 77 probands in which 16 (20.8%) harbored BMPR1A variants ([PMID:15235019]). Multiplex ligation-dependent probe amplification revealed large BMPR1A deletions in 4/27 probands ([PMID:18178612]). A founder 429 kb deletion encompassing BMPR1A has been described in Bukharin Jewish families ([PMID:31259752]). In total, >100 unrelated JPS probands with BMPR1A variants have been reported.

Segregation analysis demonstrates co-segregation of BMPR1A variants with JPS in at least 15 multiplex families, supporting a haploinsufficiency mechanism. Variant spectrum includes frameshift (e.g., c.115_116insA (p.Ser39fs)), nonsense, splice-site, missense, exon duplications (c.230+452_333+441dup1995), and large genomic deletions. Recurrent LoF alleles and population-specific founder mutations are documented.

Functional studies confirm pathogenicity: in vitro BMPR1A missense mutations (e.g., p.Cys82Tyr, p.Arg254Pro) disrupt receptor trafficking and membrane localization ([PMID:23433720]), while somatic polyps show frequent loss of heterozygosity in BMPR1A ([PMID:26171675]). Animal and cellular models of BMPR1A deficiency recapitulate epithelial dysplasia and polyp formation, consistent with receptor haploinsufficiency.

Conflict: Some patients with contiguous 10q23 deletions lack juvenile polyps but present extraintestinal features, underscoring phenotypic variability. However, sequencing and CNV analysis of BMPR1A is recommended for all suspected JPS cases, even without classic polyp histology.

Overall, BMPR1A has a Definitive association with JPS based on extensive genetic and experimental data. Genetic testing for BMPR1A variants guides surveillance and management, enabling early polyp detection and colorectal cancer prevention.

References

• Nature Genetics • 2001 • Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis PMID:11381269
• Journal of medical genetics • 2004 • The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations PMID:15235019
• Gut • 2008 • Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis PMID:18178612
• Clinical and translational gastroenterology • 2019 • Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A PMID:31259752
• The Journal of surgical research • 2013 • BMPR1A mutations in juvenile polyposis affect cellular localization PMID:23433720
• Genes, chromosomes & cancer • 2015 • Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers PMID:26171675

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