RELN and Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a prototypic inflammatory spondyloarthropathy characterized by sacroiliitis, syndesmophyte formation, and progressive axial stiffness. Despite a strong polygenic component, distinct monogenic causes of AS have not previously been reported. In a large Iranian kindred spanning multiple generations, whole-exome sequencing of three affected and two unaffected relatives uncovered a heterozygous RELN missense variant, c.7456A>G (p.Ser2486Gly), which completely co-segregates with AS under an apparent autosomal dominant model (3 affected) (PMID:32001840). The variant is absent from population databases and unreported in other AS cohorts, indicating rarity and a possible private allele status. Segregation in additional affected family members further supports pathogenicity in this pedigree. However, no unrelated probands or replication studies have been described to date, limiting the strength of genetic evidence.

Functional in vitro analyses revealed that the RELN p.Ser2486Gly substitution leads to a significant reduction in Reelin secretion in CHO-K1 and HEK-293T cells, accompanied by decreased expression of the downstream PLA2G7 gene and lower PAF-AH protein levels in THP-1 monocytes (PMID:33107310). These data support a loss-of-function mechanism by which impaired Reelin-mediated pathways may alter bone remodeling or immune modulation. No contrasting functional studies have been reported, and in silico predictions uniformly indicate deleterious impact. Taken together, the genetic and functional findings provide preliminary validation of RELN as a rare monogenic contributor to AS, though this association remains limited by single-family evidence and absence of broader cohort replication. Prospective screening of additional AS families and functional characterization in relevant cell or animal models will be required to confirm clinical validity. Key take-home: RELN c.7456A>G (p.Ser2486Gly) represents a candidate autosomal dominant variant in familial AS with potential diagnostic and therapeutic relevance pending further validation.

References

• European Journal of Human Genetics • 2020 • Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS. PMID:32001840
• Archives of Iranian Medicine • 2020 • Functional Analysis of RELN S2486G Mutation and its Contribution to Pathogenesis of Ankylosing Spondylitis. PMID:33107310

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