Human Genetics

, Volume 133, Issue 8, pp 975–984 | Cite as

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

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.

Notes

Acknowledgments

We wish to thank the family members for their willing participation and cooperation with this study. This research was supported by a grant from the Canadian Institutes of Health Research (#MOP-102758), and by the Pakistan Higher Education Commission (HEC). We declare that the authors have no competing interests for this article.

Supplementary material

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

References

  1. Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miró X, White JK, Désir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmüller J, Nürnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nürnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G (2012) Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet 91:998–1010. doi: 10.1016/j.ajhg.2012.10.011 PubMedCentralPubMedCrossRefGoogle Scholar
  2. David M, Dzamba M, Lister D, Ilie L, Brudno M (2011) SHRiMP2: sensitive yet practical short read mapping. Bioinformatics 27:1011–2101. doi: 10.1093/bioinformatics/btr046 PubMedCrossRefGoogle Scholar
  3. Deshaies RJ, Joazeiro CA (2009) RING domain E3 ubiquitin ligases. Annu Rev Biochem 78:399–434. doi: 10.1146/annurev.biochem.78.101807.093809 PubMedCrossRefGoogle Scholar
  4. Ellison JW, Rosenfeld JA, Shaffer LG (2013) Genetic basis of intellectual disability. Annu Rev Med 64:441–450. doi: 10.1146/annurev-med-042711-140053 PubMedCrossRefGoogle Scholar
  5. Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, Bauters M, Govaerts K, Vandeleur L, Van Esch H, Chelly J, Sanlaville D, van Bokhoven H, Ropers HH, Laumonnier F, Ranieri E, Schwartz CE, Abidi F, Tarpey PS, Futreal PA, Whibley A, Raymond FL, Stratton MR, Fryns JP, Scott R, Peippo M, Sipponen M, Partington M, Mowat D, Field M, Hackett A, Marynen P, Turner G, Gécz J (2008) Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am J Hum Genet 82:432–443. doi: 10.1016/j.ajhg.2007.11.002 Google Scholar
  6. Geetha TS, Michealraj KA, Kabra M, Kaur G, Juyal RC, Thelma BK (2014) Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India. Hum Mutat 35:41–44. doi: 10.1002/humu.22453 PubMedCrossRefGoogle Scholar
  7. Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM (2008) Dysregulation of large-conductance Ca(2+)-activated K(+) channel expression in nonsyndromal mental retardation due to a cereblon p. R419X mutation. Neurogenetics 9:219–223. doi: 10.1007/s10048-008-0128-2 PubMedCrossRefGoogle Scholar
  8. Homer N, Nelson SF (2010) Improved variant discovery through local re-alignment of short-read next-generation sequencing data using SRMA. Genome Biol 11:R99. doi: 10.1186/gb-2010-11-10-r99 PubMedCentralPubMedCrossRefGoogle Scholar
  9. Huang HL, Zheng WL, Zhao R, Zhang B, Ma WL (2010) FBXO31 is down-regulated and may function as a tumor suppressor in hepatocellular carcinoma. Oncol Rep 24:715–720PubMedCrossRefGoogle Scholar
  10. Kanie T, Onoyama I, Matsumoto A, Yamada M, Nakatsumi H, Tateishi Y, Yamamura S, Tsunematsu R, Matsumoto M, Nakayama KI (2012) Genetic evaluation of the role of F-box proteins in cyclin D1 degradation. Mol Cell Biol 32:590–605. doi: 10.1128/MCB.06570-11 PubMedCentralPubMedCrossRefGoogle Scholar
  11. Kaufman L, Ayub M, Vincent JB (2010) The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord 2:182–209PubMedCentralPubMedCrossRefGoogle Scholar
  12. Kishino T, Lalande M, Wagstaff J (1997) UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 15:70–73PubMedCrossRefGoogle Scholar
  13. Kumar R, Neilsen PM, Crawford J, McKirdy R, Lee J, Powell JA, Saif Z, Martin JM, Lombaerts M, Cornelisse CJ, Cleton-Jansen AM, Callen DF (2005) FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex. Cancer Res 65:11304–11313PubMedCrossRefGoogle Scholar
  14. Leonard H, Wen X (2002) The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev 8:117–134PubMedCrossRefGoogle Scholar
  15. Lin M, Wei LJ, Sellers WR, Lieberfarb M, Wong WH, Li C (2004) dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 20:1233–1240PubMedCrossRefGoogle Scholar
  16. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  17. Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, Rommens JM, Beaudet AL (1997) De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 15:74–77PubMedCrossRefGoogle Scholar
  18. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S (2011) Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil 32:419–436. doi: 10.1016/j.ridd.2010.12.018 PubMedCrossRefGoogle Scholar
  19. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. doi: 10.1101/gr.107524.110 PubMedCentralPubMedCrossRefGoogle Scholar
  20. Micale L, Fusco C, Augello B, Napolitano LM, Dermitzakis ET, Meroni G, Merla G, Reymond A (2008) Williams–Beuren syndrome TRIM50 encodes an E3 ubiquitin ligase. Eur J Hum Genet 16:1038–1049. doi: 10.1038/ejhg.2008.68 PubMedCentralPubMedCrossRefGoogle Scholar
  21. Musante L, Ropers HH (2014) Genetics of recessive cognitive disorders. Trends Genet 30:32–39. doi: 10.1016/j.tig.2013.09.008 PubMedCrossRefGoogle Scholar
  22. Nascimento RM, Otto PA, de Brouwer AP, Vianna-Morgante AM (2006) UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a novel X-linked mental retardation syndrome. Am J Hum Genet 79:549–555PubMedCentralPubMedCrossRefGoogle Scholar
  23. Pagnamenta AT, Khan H, Walker S, Gerrelli D, Wing K, Bonaglia MC, Giorda R, Berney T, Mani E, Molteni M, Pinto D, Le Couteur A, Hallmayer J, Sutcliffe JS, Szatmari P, Paterson AD, Scherer SW, Vieland VJ, Monaco AP (2011) Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability. J Med Genet 48:48–54. doi: 10.1136/jmg.2010.079426 PubMedCentralPubMedCrossRefGoogle Scholar
  24. Quaderi NA, Schweiger S, Gaudenz K, Franco B, Rugarli EI, Berger W, Feldman GJ, Volta M, Andolfi G, Gilgenkrantz S, Marion RW, Hennekam RC, Opitz JM, Muenke M, Ropers HH, Ballabio A (1997) Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet 17:285–291PubMedCrossRefGoogle Scholar
  25. Seelow D, Schuelke M, Hildebrandt F, Nürnberg P. (2009) HomozygosityMapper—an interactive approach to homozygosity mapping. Nucleic Acids Res 37(Web Server issue):W593-9. doi: 10.1093/nar/gkp369
  26. Seibenhener ML, Wooten MW (2012) Isolation and culture of hippocampal neurons from prenatal mice. J Vis Exp (65). doi: 10.3791/3634
  27. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76–85. doi: 10.1016/0003-2697(85)90442-7 PubMedCrossRefGoogle Scholar
  28. Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker sharing statistics. Am J Hum Genet 58:1323–1337PubMedCentralPubMedGoogle Scholar
  29. Sobel E, Sengul H, Weeks DE (2001) Multipoint estimation of identity-by-descent probabilities at arbitrary positions among marker loci on general pedigrees. Hum Hered 52:121–131PubMedCrossRefGoogle Scholar
  30. Sobel E, Papp JC, Lange K (2002) Detection and integration of genotyping errors in statistical genetics. Am J Hum Genet 70:496–508PubMedCentralPubMedCrossRefGoogle Scholar
  31. Sparrow SS, Cicchetti DV, Balla DA (2005) Vineland-II adaptive behavior scales: survey forms manual. AGS Publishing, Circle PinesGoogle Scholar
  32. Tarpey PS, Raymond FL, O’Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M (2007) Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet 80:345–352PubMedCentralPubMedCrossRefGoogle Scholar
  33. Vadhvani M, Schwedhelm-Domeyer N, Mukherjee C, Stegmuller J (2013) The centrosomal E3 ubiquitin ligase FBXO31-SCF regulated neuronal morphogenesis and migration. PLoS One 8:e57530. doi: 10.1371/journal.pone.0057530 PubMedCentralPubMedCrossRefGoogle Scholar
  34. Xu G, Jiang X, Jaffrey SR (2013) A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition. J Biol Chem 288:29573–29585. doi: 10.1074/jbc.M113.472092 PubMedCrossRefGoogle Scholar
  35. Yi JJ, Ehlers MD (2007) Emerging roles for ubiquitin and protein degradation in neuronal function. Pharmacol Rev 59:14–39PubMedCrossRefGoogle Scholar
  36. Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, Beier M, Hülskamp G, Guzman C, Rehder H, Beemer FA, Hamel B, Vanlieferinghen P, Gershoni-Baruch R, Vieira MW, Dumic M, Auslender R, Gil-da-Silva-Lopes VL, Steinlicht S, Rauh M, Shalev SA, Thiel C, Ekici AB, Winterpacht A, Kwon YT, Varshavsky A, Reis A (2005) Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson–Blizzard syndrome). Nat Genet 37:1345–1350PubMedCrossRefGoogle Scholar

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

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