Congenital Bone Disorders Associated with ERI1-Mediated RNA Metabolism Dysfunction: Spondylo-Epi-Metaphyseal Dysplasia Guo-Campeau Type and Beyond.

purpose of reviewThe purpose of this review is to explore the multifaceted roles of the ERI1 exoribonuclease, particularly in RNA metabolism and bone development, and to address the genotype-phenotype complexity in patients and mice with ERI1 pathogenic variants. RECENT

findingsThe 3'-to-5' exoribonuclease 1 encoded by the ERI1 gene performs a variety of biologically essential functions, including modulating RNA interference, heterochromatin formation, rRNA maturation, and histone mRNA degradation. Recently, the relationship between ERI1 variants and human skeletal dysplasia has garnered increasing attention. In a phenotypic dichotomy associated with bi-allelic ERI1 variants, patients with at least one missense pathogenic variant exhibited severe spondylo-epi-metaphyseal dysplasia (SEMD), while those with bi-allelic nonsense pathogenic variant only presented mild anomaly in digits. The biological mechanisms underlying the bone dysplasia caused by ERI1 pathogenic variants remain unknown. Although Eri1 knockout (KO) mice showed mild skeletal phenotypes, neither SEMD nor digital anomaly were found, further underscoring a complex genotype-phenotype relationship of ERI1 pathogenic variants. We systematically reviewed the advances in exploring the multiple functions of ERI1 with emphasis on its roles in RNA metabolism and skeletal development. Our review would contribute to the understanding of the phenotypic spectrum caused by ERI1 pathogenic variants and the limitations of existing disease models in revealing the corresponding pathomechanism.