Human Genetics

, Volume 133, Issue 8, pp 975–984

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

  • Asif Mir
  • Kumudesh Sritharan
  • Kirti Mittal
  • Nasim Vasli
  • Carolina Araujo
  • Talal Jamil
  • Muhammad Arshad Rafiq
  • Zubair Anwar
  • Anna Mikhailov
  • Sobiah Rauf
  • Huda Mahmood
  • Abdul Shakoor
  • Sabir Ali
  • Joyce So
  • Farooq Naeem
  • Muhammad Ayub
  • John B. Vincent
Original Investigation

DOI: 10.1007/s00439-014-1438-0

Cite this article as:
Mir, A., Sritharan, K., Mittal, K. et al. Hum Genet (2014) 133: 975. doi:10.1007/s00439-014-1438-0

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.

Supplementary material

439_2014_1438_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Asif Mir
    • 1
  • Kumudesh Sritharan
    • 2
  • Kirti Mittal
    • 2
  • Nasim Vasli
    • 2
  • Carolina Araujo
    • 2
    • 3
  • Talal Jamil
    • 1
  • Muhammad Arshad Rafiq
    • 2
  • Zubair Anwar
    • 1
  • Anna Mikhailov
    • 2
  • Sobiah Rauf
    • 1
  • Huda Mahmood
    • 2
  • Abdul Shakoor
    • 4
  • Sabir Ali
    • 5
  • Joyce So
    • 6
    • 7
    • 8
  • Farooq Naeem
    • 9
    • 10
  • Muhammad Ayub
    • 9
    • 10
  • John B. Vincent
    • 2
    • 11
    • 12
  1. 1.Human Molecular Genetics Lab, Department of Bioinformatics and BiotechnologyFBAS, International Islamic UniversityIslamabadPakistan
  2. 2.Neurogenetics Section, Molecular Neuropsychiatry and Development Lab, The Campbell Family Brain Research InstituteThe Centre for Addiction and Mental Health (CAMH)TorontoCanada
  3. 3.Federal University of Rio Grande do NorteNatalBrazil
  4. 4.Department of PsychiatryQuaid-e-Azam Medical CollegeBahawalpurPakistan
  5. 5.Department of NeurologyQuaid-e-Azam Medical CollegeBahawalpurPakistan
  6. 6.Department of Neuroscience ResearchCAMHTorontoCanada
  7. 7.The Fred A. Litwin and Family Centre in Genetic MedicineUniversity Health Network and Mount Sinai HospitalTorontoCanada
  8. 8.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  9. 9.Department of PsychiatryQueen’s UniversityKingstonCanada
  10. 10.Lahore Institute of Research and DevelopmentLahorePakistan
  11. 11.Department of PsychiatryUniversity of TorontoTorontoCanada
  12. 12.Institute of Medical ScienceUniversity of TorontoTorontoCanada