Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad; Hu, Hao; Wienker, Thomas F.; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka E L M; Brouwer, Arjan P.M. de; Veltman, Joris A.; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; Bokhoven, Hans van

doi:10.1038/ejhg.2015.148

Cited by 18 publications

(17 citation statements)

References 32 publications

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“…The gene products of both genes are involved in tRNAaminoacylation and we could confirm that both are well expressed in tissues relevant for memory and learning in the mature brain. Together with AIMP1, which we have recently found to be implicated in ID without neurodegeneration (Iqbal et al, 2016), there are now at least three genes with a role in tRNA-aminoacylation that are apparently relevant for human cognition.…”

Section: Discussionmentioning

confidence: 97%

“…With SARS , WARS2 , and the previously implicated AIMP1 , a non‐catalytic component of the multi‐tRNA synthetase complex and modulator of aminoacylation activity of cytoplasmic arginyl‐tRNA synthase RRS (Iqbal et al., ) there are now at least three genes involved in tRNA‐aminoacylation that play a role in the pathology of hereditary cognitive disorders. In this context, it is worthwhile mentioning that various tRNA‐modifiers were already found to play a role in the etiology of ID as well (see Balke, Kuss, & Muller, for review).…”

Section: Discussionmentioning

confidence: 99%

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Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

et al. 2017

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Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNA concentrations. The mutant protein was predicted to be unstable, which could be substantiated by investigating ectopic mutant SARS in transfected HEK293T cells. In the second family, we found a compound heterozygous genotype of the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, comprising a nonsense mutation (c.325delA, p.Ser109Alafs*15), which very likely entails nonsense-mediated mRNA decay and a missense mutation (c.37T>G, p.Trp13Gly). The latter affects the mitochondrial localization signal of WARS2, causing protein mislocalization. Including AIMP1, which we have recently implicated in the etiology of ID, three genes with a role in tRNA-aminoacylation are now associated with this condition. We therefore suggest that the functional integrity of tRNAs in general is an important factor in the development and maintenance of human cognitive functions.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

et al. 2017

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“…AIMP1 act as a noncatalytic component of a tRNA multi-synthetase complex (MSC). The MSC contains three noncatalytic proteins (AIMP1, AIMP2, AIMP3), joined to nine catalytic aminoacyl-tRNA synthetases (ARS) [21,22]. Studies have shown that AIMP1 expression is observed in hippocampus and spinal horn [23].…”

Section: Discussionmentioning

confidence: 99%

“…The AIMP1 interacts with neurofilament light subunit helping to optimally modulate neurofilament light phosphorylation. The neurofilaments play crucial role in the neuron development and function [22,24]. Homozygous mutation in the AIMP1 gene cause hypomyelinating leukodystrophy-3 (HLD3) which is characterized by global developmental delay, speech impairment, and peripheral spasticity associated with decreased myelination in the central nervous system [25].…”

Section: Discussionmentioning

confidence: 99%

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Pathological Variants of Aminoacyl-tRNA-synthetase-Interacting Multifunctional Protein 1 Gene in an Iranian Consanguineous Family With Autosomal Recessive Intellectual Disability

Cheraghi

Moghbelinejad

Najafipour

2019

J. Qazvin Univ. Med. Sci.

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Background Intellectual disability (ID) is one of the most common neurodevelopment disorders that caused by both environment and genetic factors. Genetic diseases account for 50% of ID incidents and have important role in its development. One of the most important risk factors of ID in most countries is consanguineous marriage. In consanguineous families, the risk of developing autosomal recessive ID is 3.6-fold higher. There is high prevalence of consanguineous marriage in Iran (about 40 %). Objective In this study, we aimed to investigate the pathological variants of aminoacyl-trna-synthetaseinteracting multifunctional protein 1 (AIMP1) in an Iranian consanguineous family with multiple-ID af� fected members. Methods this analytical epidemiological study, whole exome sequencing method was used to examine the molecular etiology in two female ID patients of a consanguineous family living in Qazvin, Iran. Sanger sequencing was carried out for validating potential causative variants in patients, and co-segregation analysis for other family members. Findings A stop-gain variant (p. Arg158*) in the AIMP1 gene was identified as pathological variant in the study family according to American College of Medical Genetics and Genomics guidelines. Conclusion The found variant in the AIMP1 gene caused truncated protein and clinical manifestations such as developmental delay, ID, spastic paraplegia, thin corpus callosum, and speech impairment in the two patients.

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

et al. 2021

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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 TyrRSMini 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.

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Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

Cited by 18 publications

References 32 publications

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

Pathological Variants of Aminoacyl-tRNA-synthetase-Interacting Multifunctional Protein 1 Gene in an Iranian Consanguineous Family With Autosomal Recessive Intellectual Disability

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

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