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Osteogenesis imperfecta type 10 and the cellular scaffolds underlying common immunological diseases

Genes & Immunity (2024)Cite this article

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Abstract

Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.

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Fig. 1: Interactions that regulate osteoclast fate from three different perspectives.
Fig. 2: The alignment of the vLRR in HSP with RHIM in cell death effector proteins.
Fig. 3: vLRR and RHIM crystal structures showing the protein backbone as a rope and vLRR by a space-filling representations.

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Not applicable as all the data synthesized in this review are available through the sources cited.

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Acknowledgements

Thanks to the authors who generated the experimental data on which this synthesis is based.

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    Alan Herbert

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Herbert, A. Osteogenesis imperfecta type 10 and the cellular scaffolds underlying common immunological diseases. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00277-4

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