Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.
Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
J Mol Med (Berl). 2021 Dec;99(12):1755-1768. doi: 10.1007/s00109-021-02124-9. Epub 2021 Sep 18.
Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRS and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM_003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)-retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)-mild ID, p.(Pro167Thr)-high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders. KEY MESSAGES: The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder. p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions. Phenotypic heterogeneity associates with the different affected YARS1 domains. Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders.
氨基酸酰-tRNA 合成酶（ARS1）中的致病性变异导致多种常染色体隐性疾病。酪氨酸 tRNA 合成酶（TyrRS）由 YARS1（胞质，OMIM*603,623）编码，负责将酪氨酸与特定的 tRNA 连接。除了酶结构域外，TyrRS 还有两个额外的功能结构域（N 端 TyrRS 和 C 端 EMAP-II 样结构域），赋予细胞因子样功能。YARS1 中的突变与常染色体显性遗传的 Charcot-Marie-Tooth（CMT）神经病 C 型和一组常染色体隐性遗传的多系统疾病有关。我们从 6 个家系中发现了 12 名个体，他们携带 YARS1 中反复出现的纯合错义变异 c.1099C>T;p.(Arg367Trp)（NM_003680.3）。这种变异导致一种多系统疾病，表现为发育迟缓、小头畸形、生长不良、身材矮小、肌肉张力减退、共济失调、脑异常、小细胞性贫血、肝肿大和甲状腺功能减退。计算机分析表明，p.(Arg367Trp) 不会影响负责酶偶联的催化结构域，但会使细胞因子样 C 端结构域不稳定。与 p.(Arg367Trp) 相关的表型与位于 TyrRS 不同功能结构域的其他双等位致病性变异不同，所有这些变异都显示出一些共同的，但也有不同的临床特征[（例如，p.(Phe269Ser)-视网膜异常，p.(Pro213Leu)/p.(Gly525Arg)-轻度智力障碍，p.(Pro167Thr)-高死亡率）]。ARS1 相关疾病的广泛临床谱与影响 ARS1 各种非典型结构域的突变有关，而蛋白翻译受损可能不是 YARS1 和 ARS1 相关神经发育障碍的唯一致病机制。 关键信息： YARS1 中的错义变异 p.(Arg367Trp) 导致一种独特的多系统疾病。 p.(Arg367Trp) 影响具有细胞因子样功能的非典型结构域。表型异质性与受影响的 YARS1 结构域不同有关。蛋白翻译受损可能不是 ARS1 相关疾病的唯一机制。
