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A Novel Single-Nucleotide Deletion (c.1020delA) in NSUN2 Causes Intellectual Disability in an Emirati Child

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Abstract

Intellectual disability (ID) is a major public health burden on most societies with significant socioeconomic costs. It has been shown that genetic mutations in numerous genes are responsible for a proportion of hereditary forms of ID. NOP2/Sun transfer RNA (tRNA) methyltransferase family member 2 encoded by NSUN2 gene is a highly conserved protein and has been shown to cause autosomal recessive ID type 5 (MRT5). In this study, we recruited an Emirati consanguineous family with a patient diagnosed with ID. Whole-exome sequencing revealed a homozygous variant c.1020delA in NSUN2 gene. The variants segregated in an autosomal recessive mode of inheritance in the family. This variant is novel and causes a frameshift and premature stop codon. At the messenger RNA (mRNA) level, relative expression analysis showed a decreased level of NSUN2 mRNA in the affected child compared to a healthy individual. Mutation prediction analysis and clinical investigation confirmed the pathogenic nature of the identified variant. We therefore conclude that c.1020delA mutation in NSUN2 is most likely the cause of ID in our patient.

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References

  • Abbasi-Moheb L, Mertel S, Gonsior M, Nouri-Vahid L, Kahrizi K, Cirak S, Wieczorek D et al (2012) Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am J Hum Genet 90:847–55. doi:10.1016/j.ajhg.2012.03.021

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Alvarado S, Fernald RD, Storey KB, Moshe S (2014) The dynamic nature of DNA methylation: a role in response to social and seasonal variation. Integr Comp Biol 54(1):68–76. doi:10.1093/icb/icu034

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Basel-Vanagaite L (2007) Genetics of autosomal recessive non-syndromic mental retardation: recent advances. Clin Genet 72:167–174. doi:10.1111/j.1399-0004.2007.00881.x

    Article  CAS  PubMed  Google Scholar 

  • Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ (2002) Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes 51:2301–2305. doi:10.2337/diabetes.51.7.2301

    Article  CAS  PubMed  Google Scholar 

  • Blanco S, Frye M (2014) Role of RNA methyltransferases in tissue renewal and pathology. Curr Opin Cell Biol 31:1–7. doi:10.1016/j.ceb.2014.06.006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chi L, Delgado-Olguín P (2013) Expression of NOL1/NOP2/sun Domain (Nsun) RNA methyltransferase family genes in early mouse embryogenesis. Gene Expr Patterns 13:319–27. doi:10.1016/j.gep.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  • De Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT et al (2012) Diagnostic exome sequencing in persons with severe intellectual disability. New England Journal of Medicine. doi:10.1056/NEJMoa1206524

  • Fahiminiya S, Almuriekhi M, Nawaz Z, Staffa A, Lepage P, Ali R, Hashim L et al (2014) Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar. Clin Genet 86:134–141. doi:10.1111/cge.12280

    Article  CAS  PubMed  Google Scholar 

  • Fisher, M. H., M. M. Griffin, and R. M. Hodapp (2011) Intellectual disabilities (mental retardation). Encyclopedia of adolescence. Vol. 1. Elsevier Inc. doi: 10.1016/B978-0-12-373951-3.00025-9

  • Frischmeyer PA, Dietz HC (1999) Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 8(10):1893–1900

    Article  CAS  PubMed  Google Scholar 

  • Frye M, Watt FM (2006) The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Curr Biol 16:971–981. doi:10.1016/j.cub.2006.04.027

    Article  CAS  PubMed  Google Scholar 

  • Hussain S, Benavente SB, Nascimento E, Dragoni I, Kurowski A, Gillich A, Humphreys P, Frye M (2009) The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability. J Cell Biol 186(1):27–40. doi:10.1083/jcb.200810180

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hussain S, Sajini AA, Blanco S, Sabine D, Lombard P, Sugimoto Y, Paramor M et al (2013a) NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell Rep 4(2):255–61. doi:10.1016/j.celrep.2013.06.029

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hussain S, Tuorto F, Menon S, Blanco S, Cox C, Flores VJ, Watt S, Nobuaki R, Frank Lyko K, Frye M (2013b) The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation. Mol Cell Biol 33(8):1561–1570. doi:10.1128/MCB.01523-12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jahnavi S, Poovazhagi V, Kanthimathi S, Gayathri V, Mohan V, Radha V (2014) EIF2AK3 mutations in South Indian children with permanent neonatal diabetes mellitus associated with Wolcott-Rallison syndrome. Pediatr Diabetes 15(1):313–318. doi:10.1111/pedi.12089

    Article  CAS  PubMed  Google Scholar 

  • Khan MA, Rafiq MA, Noor A, Hussain S, Flores JV, Rupp V, Vincent AK et al (2012) Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am J Hum Genet 90(5):856–63. doi:10.1016/j.ajhg.2012.03.023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the sift algorithm. Nat Protoc 4(7):1073–1081. doi:10.1038/nprot.2009.86

    Article  CAS  PubMed  Google Scholar 

  • Kuss AW, Masoud G, Kimia K, Andreas T, Farkhondeh B, Hossein V, Lia AM et al (2011) Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots. Hum Genet 129:141–148. doi:10.1007/s00439-010-0907-3

    Article  PubMed  Google Scholar 

  • Martinez FJ, Lee JH, Lee JE, Blanco S, Nickerson E, Gabriel S, Frye M, Al-Gazali L, Gleeson JG et al (2012) Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J Med Genet 49(6):380–385. doi:10.1136/jmedgenet-2011-100686

    Article  CAS  PubMed  Google Scholar 

  • Miller JN, David AP (2014) Nonsense-mediated decay in genetic disease: friend or foe? Mutation Research/Reviews in Mutation Research 762. Elsevier B.V.: 52–64. doi: 10.1016/j.mrrev.2014.05.001

  • Hossein N, Motazacker MM, Garshasbi M, Kahrizi K, Andreas T, Wei C, Farkhondeh B et al (2007) Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci. Hum Genet 121:43–48. doi:10.1007/s00439-006-0292-0

    Article  Google Scholar 

  • Paronetto MP, Sette C (2010) Role of RNA-binding proteins in mammalian spermatogenesis. Int J Androl 33:2–12. doi:10.1111/j.1365-2605.2009.00959.x

    Article  CAS  PubMed  Google Scholar 

  • Perego, Lucia, Marina Cardellini, Maria Adelaide Marini, Simona Frontoni, Francesco Andreozzi, Angela Sciacqua, Davide Lauro, et al. (2004) Brief Genetics Report 53 (July): 1905–10

  • Prieto García F (1998) Genetics of mental retardation. Neurologia (Barcelona, Spain) 13(20):218–222. doi:10.4103/0019-5359.16820

    Google Scholar 

  • Reis AF, Kannengiesser C, Jennane F, Manna TD, Cheurfa N, Oudin C, Savoldelli RD et al (2011) Two novel mutations in the EIF2AK3 gene in children with Wolcott-Rallison syndrome. Pediatr Diabetes 12(April 2010):187–191. doi:10.1111/j.1399-5448.2010.00679.x

    Article  PubMed  Google Scholar 

  • Ropers HH (2008) Genetics of intellectual disability. Curr Opin Genet Dev 18(1):241–50. doi:10.1016/j.gde.2008.07.008

    Article  CAS  PubMed  Google Scholar 

  • Shea SE (2012) Intellectual disability (mental retardation). Pediatr Rev 33(3):110–121. doi:10.1542/pir.33-3-110

    Article  PubMed  Google Scholar 

  • Tuorto F, Liebers R, Musch T, Schaefer M, Hofmann S, Kellner S, Frye M, Helm M, Stoecklin G, Lyko F (2012) RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat Struct Mol Biol 19(9):900–905. doi:10.1038/nsmb.2357

    Article  CAS  PubMed  Google Scholar 

  • Venselaar H, Te Beek TAH, Kuipers RKP, Hekkelman ML, Gert V (2010) Protein structure analysis of mutations causing inheritable diseases. an e-science approach with life scientist friendly interfaces. BMC Bioinf 11(1):548. doi:10.1186/1471-2105-11-548

    Article  Google Scholar 

  • Winnepenninckx B, Rooms L, Frank Kooy R (2003) Mental retardation: a review of the genetic causes. Br J Dev Disabil 49(96):29–44. doi:10.1179/096979503799104138

    Article  Google Scholar 

  • Zhang, Xiaotian, Zhenyun Liu, Jie Yi, Hao Tang, Junyue Xing, Minqwei Yu, Tanjun Tong, Yongfeng Shang, Myriam Gorospe, and Wengong Wang (2012) The tRNA methyltransferase NSun2 stabilizes p16INK4 mRNA by methylating the 3′-untranslated region of p16. Nature Communications. doi:10.1038/ncomms1692

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Authors and Affiliations

  1. Department of Pathology, College of Medicine and Heath Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates

    Makanko Komara, Salma Ben-Salem & Bassam R. Ali

  2. Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates

    Aisha M. Al-Shamsi

  3. Department of Pediatrics, College of Medicine and Heath Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates

    Lihadh Al-Gazali

Authors
  1. Makanko Komara
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  2. Aisha M. Al-Shamsi
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  3. Salma Ben-Salem
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  4. Bassam R. Ali
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  5. Lihadh Al-Gazali
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Correspondence to Lihadh Al-Gazali.

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Komara, M., Al-Shamsi, A.M., Ben-Salem, S. et al. A Novel Single-Nucleotide Deletion (c.1020delA) in NSUN2 Causes Intellectual Disability in an Emirati Child. J Mol Neurosci 57, 393–399 (2015). https://doi.org/10.1007/s12031-015-0592-8

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  • DOI: https://doi.org/10.1007/s12031-015-0592-8

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