The SNP rs4252548 (R112H) which is associated with reduced human height compromises the stability of IL-11

Abstract

Height is a complex human phenotype that is influenced by variations in a high number of genes. Recently, a single nucleotide polymorphism (SNP) within IL11 (rs4252548) has been described to be associated with height in adults of European ancestry. This coding SNP leads to the exchange of Arg-112 to His-112 within the cytokine Interleukin-11 (IL-11), which has a well-established role in osteoclast development and bone turnover. The functional consequences of the R112H mutation are unknown so far. In this study, we show by molecular replacement that Arg-112 does not participate in binding of IL-11 to its receptors IL-11R and glycoprotein 130 (gp130). Recombinant IL-11 R112H expressed in E. coli displays a correct four-helix-bundle folding topology, and binds with similar affinity to IL-11R and the IL-11/IL-11R/gp130 complex. IL-11 R112H induces cell proliferation and phosphorylation of the downstream transcription factor STAT3 indistinguishable from IL-11. However, IL-11 R112H fails to support the survival of osteoclast progenitor cells and is less thermally stable, which is caused by the loss of the positive charge on the protein surface since protonation of the histidine side chain recovers stability.

RNA Sequencing Reveals Interacting Key Determinants of Osteoarthritis Acting in Subchondral Bone and Articular Cartilage: Identification of IL11 and CHADL as Attractive Treatment Targets

“…IL11 , encoding interleukin‐11 (IL‐11), is known for its role in bone remodeling, and lack of IL‐11 function is associated with impaired bone formation (38). Notably, IL11 was recently proposed as a potential therapeutic target for OA in cartilage (6), since the OA risk allele rs4252548‐T, a missense variant p.Arg112His, acts via reduced function of the IL‐11 protein.…”

RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage

“…However, when stratifying for joint site, we found CHADL being DE in particularly the knee subchondral bone, suggesting CHADL is a potential drug target for knee OA exclusively. IL11, encoding Interleukin 11, is known for its role in bone remodelling and lack of IL11 function is associated with impaired bone formation [36].…”

Mutations in Craniosynostosis Patients Cause Defective Interleukin-11 Receptor Maturation and Drive Craniosynostosis-like Disease in Mice

“…Importantly, the IL-11R is also found on osteoblasts, and signaling via the IL-11R is required for normal bone remodeling in mice. Consequently, Il11ra À/À mice have reduced length of the long bones (Sims et al, 2005), and a SNP in IL-11, which is associated with reduced adult height in humans, reduces the biological activity of the cytokine (Lokau et al, 2018).…”