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Free keywords:
Adult
Amino Acid Sequence
Child
Computer Simulation
Cytokines/chemistry/*genetics
Exome/genetics
Family
Female
*Genes, Recessive
Haplotypes/genetics
High-Throughput Nucleotide Sequencing
Homozygote
Humans
Intellectual Disability/*complications/*genetics
Male
Molecular Sequence Data
Mutation
Mutation, Missense/*genetics
Neoplasm Proteins/chemistry/*genetics
Nerve Degeneration/*complications/*genetics
Pedigree
Protein Structure, Secondary
RNA-Binding Proteins/chemistry/*genetics
Reproducibility of Results
Young Adult
Abstract:
AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.
