Original Investigation

Human Genetics

, Volume 133, Issue 8, pp 975-984

First online:

Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family

  • Asif MirAffiliated withHuman Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University
  • , Kumudesh SritharanAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)
  • , Kirti MittalAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)
  • , Nasim VasliAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)
  • , Carolina AraujoAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)Federal University of Rio Grande do Norte
  • , Talal JamilAffiliated withHuman Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University
  • , Muhammad Arshad RafiqAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)
  • , Zubair AnwarAffiliated withHuman Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University
  • , Anna MikhailovAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)
    • , Sobiah RaufAffiliated withHuman Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University
    • , Huda MahmoodAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)
    • , Abdul ShakoorAffiliated withDepartment of Psychiatry, Quaid-e-Azam Medical College
    • , Sabir AliAffiliated withDepartment of Neurology, Quaid-e-Azam Medical College
    • , Joyce SoAffiliated withDepartment of Neuroscience Research, CAMHThe Fred A. Litwin and Family Centre in Genetic Medicine, University Health Network and Mount Sinai HospitalDepartment of Laboratory Medicine and Pathobiology, University of Toronto
    • , Farooq NaeemAffiliated withDepartment of Psychiatry, Queen’s UniversityLahore Institute of Research and Development
    • , Muhammad AyubAffiliated withDepartment of Psychiatry, Queen’s UniversityLahore Institute of Research and Development
    • , John B. VincentAffiliated withNeurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research Institute, The Centre for Addiction and Mental Health (CAMH)Department of Psychiatry, University of TorontoInstitute of Medical Science, University of Toronto Email author 

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Abstract

In this study, we have performed autozygosity mapping on a large consanguineous Pakistani family segregating with intellectual disability. We identified two large regions of homozygosity-by-descent (HBD) on 16q12.2–q21 and 16q24.1–q24.3. Whole exome sequencing (WES) was performed on an affected individual from the family, but initially, no obvious mutation was detected. However, three genes within the HBD regions that were not fully captured during the WES were Sanger sequenced and we identified a five base pair deletion (actually six base pairs deleted plus one base pair inserted) in exon 7 of the gene FBXO31. The variant segregated completely in the family, in recessive fashion giving a LOD score of 3.95. This variant leads to a frameshift and a premature stop codon and truncation of the FBXO31 protein, p.(Cys283Asnfs*81). Quantification of mRNA and protein expression suggests that nonsense-mediated mRNA decay also contributes to the loss of FBXO31 protein in affected individuals. FBXO31 functions as a centrosomal E3 ubiquitin ligase, in association with SKP1 and Cullin-1, involved in ubiquitination of proteins targeted for degradation. The FBXO31/SKP1/Cullin1 complex is important for neuronal morphogenesis and axonal identity. FBXO31 also plays a role in dendrite growth and neuronal migration in developing cerebellar cortex. Our finding adds further evidence of the involvement of disruption of the protein ubiquitination pathway in intellectual disability.