title: Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration.
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.
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Zafar
authors.identifier: http://orcid.org/0000-0002-6387-8019
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Püttmann
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Musante
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Attia
authors.initials: A
authors.lastname: Razzaq
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Muhammad Yasir
authors.initials: MY
authors.lastname: Zahoor
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Fattahi
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.|Kariminejad-Najmabadi Pathology & Genetics Center Tehran, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.|Allama Iqbal Medical College, Lahore, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D003198:Computer Simulation; D016207:Cytokines / Q000737:chemistry / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D005808:Genes, Recessive; D006239:Haplotypes / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D009410:Nerve Degeneration / Q000150:complications* / Q000235:genetics*; D010375:Pedigree; D017433:Protein Structure, Secondary; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1