Biallelic missense variants found in the ERI1 gene result in disrupted ribosome biogenesis, causing a specific and previously unreported type of bone and cartilage disorder. This discovery was made by an international study including researchers at the Institute of Human Genetics Göttingen. The study, published in the American Journal of Human Genetics, also revealed for the first time for a recessive disease that missense variants may lead to a more severe clinical phenotype than null variants in the same gene. Patients carrying missense variants in ERI1 exhibited a severe form of spondyloepimetaphyseal dysplasia, a skeletal disorder characterized by spine and long tubular bone malformation, while patients with biallelic null variants had a milder phenotype with mild intellectual disability and digital malformations.

ERI1 is an exoribonuclease, which means it is an enzyme responsible for breaking down RNA molecules. In humans, its precise biological role is not clear. The researchers performed functional investigations in various models, including a mouse model and patient-derived induced pluripotent stem cells differentiated into cartilage cells. Their findings revealed that ERI1 is involved in the regulation of skeletal and cartilage development. Impaired protein function and downstream effects altering RNA metabolism led to disrupted ribosome biogenesis, the process of assembling ribosomes. Depending on the type of genetic variant, the complete absence of ERI1 (null variant) or loss of a specific protein region (missense variant) have different implications for cellular processes, causing distinct clinical manifestations in affected individuals.