The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

Abstract

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^Mini 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.

Keywords: Aminoacyl-tRNA synthetases (ARS1); Functional protein domains; Multisystem diseases; Neurodevelopmental disorders; Novel disease genes; Phenotypic heterogeneity.

Fig. 1

a Organization of the functional domains of the three domains of human TyrRS and biallelic variants reported in the literature. TyrRS has three domains: (i) The catalytic N-terminal domain is essential for aminoacylation of tRNA. As a monomeric fragment, the N-terminal domain has cytokine activity and the ELR motif is critical for this activity. (ii) tRNA anti-codon-binding domain. (iii) The C-terminal EMAP-II-like domain that was shown to be dispensable for aminoacylation. The heptapeptide sequence within this domain is critical for the cytokine activity. The homozygous variants p.(Pro167Thr) and p.(Pro213Leu) reside in the catalytic domain, harboring to the critical ELR motif, while most of the other variants reside outside this domain. All five heterozygous mutations causing Charcot-Marie-Tooth neuropathy reside in the catalytic domain. b Structure of the C-terminal domain of TyrRS shown as backbone representation indicating the elements of secondary structure. Arg367 is shown in space-filled presentation and colored according to the atom types. The heptapeptide sequence stretch critical for the cytokine activity (residues 371–377) is shown in blue. c Structural role of Arg367 in TyrRS: In the wild-type, Arg367 forms a salt-bridge to Asp478 (indicated by green dotted lines). d In the p.(Arg367Trp) mutant, the bulky uncharged tryptophan cannot form an electrostatic interaction resulting in domain destabilization. c + d Arg367/Asp478 are shown in stick presentation. e Multi-species amino acid alignment indicates that Arg367 is highly conserved in mammals and down to zebrafish (Danio rerio), but not in the western clawed frog (Xenopus tropicalis) [23]. f Amino acid alignment of the C-terminal EMAP-II-like domain of TyrRS compared to AIMP1. The corresponding residues Arg367 and Asp478 are conserved in both domains. TyrRS, tyrosine tRNA synthetase; AIMP1, aminoacyl-tRNA synthetase complex interacting multifunctional protein 1

Fig. 2

a Pedigrees of affected individuals with homozygous p.(Arg367Trp) in YARS1. Individuals J and K had been reported within a large cohort of consanguineous families with ID [15]. Individual L additionally has two unaffected half-siblings (not depicted). b–h Facial features of individuals (A + B, F + G + H, I, and L). b Individual A (family 1:II-1) at age of A 11 and 15 years, c Individual B (family 1:II-2) at age of 7 and 9 years, d Individual I (family 4:II-1) at age of 7 years, e Individual F (Family 3:II-3) at age of 3 years, f Individual H (family 3:II-5), g Individual G (family 3:II-4) at age of 5 years. h Individual L (Family 6:II-41) at age of 3.5 years. Facial dysmorphic features including deep set eyes (b, c, d, g, h), sparse hair (e–h), a long nose (b-d), a flat nasal bridge (b–d), full cheeks (E − G), long columella (c–d, f–g), flat philtrum (b–h), open mouth appearance (b, d–h), low set (1), and large ears (b–d, h), together resembling progeroid-like appearance (b–h). i Axial sequences (head MRI) of individuals I, G, and F showing wide lateral ventricles as a sign of diffuse cerebral volume due to periventricular white matter loss, j Sagittal sequences (head MRI) of individuals I (2y), G (2y), and F (2y) (from left to right) showing thinning of corpus callosum