Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans

• Published in: American journal of human genetics Vol. 110; no. 7; pp. 1068 - 1085
• Main Authors: Guo, Long, Salian, Smrithi, Xue, Jing-yi, Rath, Nicola, Rousseau, Justine, Kim, Hyunyun, Ehresmann, Sophie, Moosa, Shahida, Nakagawa, Norio, Kuroda, Hiroshi, Clayton-Smith, Jill, Wang, Juan, Wang, Zheng, Banka, Siddharth, Jackson, Adam, Zhang, Yan-min, Wei, Zhen-jie, Hüning, Irina, Brunet, Theresa, Ohashi, Hirofumi, Thomas, Molly F., Bupp, Caleb, Miyake, Noriko, Matsumoto, Naomichi, Mendoza-Londono, Roberto, Costain, Gregory, Hahn, Gabriele, Di Donato, Nataliya, Yigit, Gökhan, Yamada, Takahiro, Nishimura, Gen, Ansel, K Mark, Wollnik, Bernd, Hrabě de Angelis, Martin, Mégarbané, André, Rosenfeld, Jill A., Heissmeyer, Vigo, Ikegawa, Shiro, Campeau, Philippe M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.07.2023
• Subjects: ERI1; exoribonuclease; Exoribonucleases - genetics; Histones - genetics; Humans; Mutation, Missense - genetics; ribosomopathy; RNA; RNA, Messenger - genetics; RNA, Ribosomal, 5.8S; short stature; skeletal dysplasia; spondyloepimetaphyseal dysplasia; ribosomopathy; short stature; exoribonuclease; spondyloepimetaphyseal dysplasia; ERI1; skeletal dysplasia
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2023.06.001

ERI1 is a 3′-to-5′ exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3′ end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis. Our study uncovers a ribosomopathy-related skeletal dysplasia caused by missense mutations in ERI1, which encodes an exoribonuclease. The findings set a precedent showing a more severe effect of missense alleles than null alleles within recessive genetic diseases and imply that ERI1-mediated RNA metabolism regulates development and homeostasis of human cartilage.