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Guo, L.* ; Salian, S.* ; Xue, J.y.* ; Rath, N. ; Rousseau, J.* ; Kim, H.* ; Ehresmann, S.* ; Moosa, S.* ; Nakagawa, N.* ; Kuroda, H.* ; Clayton-Smith, J.* ; Wang, J.* ; Wang, Z.* ; Banka, S.* ; Jackson, A.* ; Zhang, Y.m.* ; Wei, Z.j.* ; Hüning, I.* ; Brunet, T.* ; Ohashi, H.* ; Thomas, M.F.* ; Bupp, C.* ; Miyake, N.* ; Matsumoto, N.* ; Mendoza-Londono, R.* ; Costain, G.* ; Hahn, G.* ; di Donato, N.* ; Yigit, G.* ; Yamada, T.* ; Nishimura, G.* ; Ansel, K.M.* ; Wollnik, B.* ; Hrabě de Angelis, M. ; Megarbane, A.* ; Rosenfeld, J.A.* ; Heissmeyer, V. ; Ikegawa, S.* ; Campeau, P.M.*

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

Am. J. Hum. Genet. 110, 1068-1085 (2023)
DOI PMC
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Eri1 ; Exoribonuclease ; Ribosomopathy ; Short Stature ; Skeletal Dysplasia ; Spondyloepimetaphyseal Dysplasia; Gene-expression; Rna; Eri1; Establishment; Replication; Variants; Ribosome; Homolog; Disease; Yeast
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 110, Issue: 7, Pages: 1068-1085 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Abteilung für Molekulare Immunregulation (AMIR)
Institute of Experimental Genetics (IEG)