Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.
Am J Hum Genet
; 110(7): 1068-1085, 2023 07 06.
Article
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| MEDLINE
| ID: mdl-37352860
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Histonas
/
Exorribonucleasas
Límite:
Humans
Idioma:
En
Revista:
Am J Hum Genet
Año:
2023
Tipo del documento:
Article