Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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
Аннотация
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.