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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2013

Open Access 01-12-2013 | Research

Intellectual disability associated with a homozygous missense mutation in THOC6

Authors: Chandree L Beaulieu, Lijia Huang, A Micheil Innes, Marie-Andree Akimenko, Erik G Puffenberger, Charles Schwartz, Paul Jerry, Carole Ober, Robert A Hegele, D Ross McLeod, Jeremy Schwartzentruber, Jacek Majewski, Dennis E Bulman, Jillian S Parboosingh, Kym M Boycott, FORGE Canada Consortium

Published in: Orphanet Journal of Rare Diseases | Issue 1/2013

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Abstract

Background

We recently described a novel autosomal recessive neurodevelopmental disorder with intellectual disability in four patients from two related Hutterite families. Identity-by-descent mapping localized the gene to a 5.1 Mb region at chromosome 16p13.3 containing more than 170 known or predicted genes. The objective of this study was to identify the causative gene for this rare disorder.

Methods and results

Candidate gene sequencing followed by exome sequencing identified a homozygous missense mutation p.Gly46Arg, in THOC6. No other potentially causative coding variants were present within the critical region on chromosome 16. THOC6 is a member of the THO/TREX complex which is involved in coordinating mRNA processing with mRNA export from the nucleus. In situ hybridization showed that thoc6 is highly expressed in the midbrain and eyes. Cellular localization studies demonstrated that wild-type THOC6 is present within the nucleus as is the case for other THO complex proteins. However, mutant THOC6 was predominantly localized to the cytoplasm, suggesting that the mutant protein is unable to carry out its normal function. siRNA knockdown of THOC6 revealed increased apoptosis in cultured cells.

Conclusion

Our findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment.
Appendix
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Literature
1.
Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P: Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011, 478: 57-63. 10.1038/nature10423.PubMedCrossRef
2.
Hostetler JA, Opitz JM, Reynolds JF: History and relevance of the Hutterite population for genetic studies. Am J Med Genet. 1985, 22: 453-462. 10.1002/ajmg.1320220303.PubMedCrossRef
3.
Boycott KM, Parboosingh JS, Chodirker BN, Lowry RB, McLeod DR, Morris J, Greenberg CR, Chudley AE, Bernier FP, Midgley J: Clinical genetics and the Hutterite population: a review of Mendelian disorders. Am J Med Genet Part A. 2008, 146A: 1088-1098. 10.1002/ajmg.a.32245.PubMedCrossRef
4.
Boycott KM, Beaulieu C, Puffenberger EG, McLeod DR, Parboosingh JS, Innes AM: A novel autosomal recessive malformation syndrome associated with developmental delay and distinctive facies maps to 16ptel in the Hutterite population. Am J Med Genet Part A. 2010, 152A: 1349-1356.PubMed
5.
Kaufman L, Ayub M, Vincent JB: The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord. 2010, 2: 182-209. 10.1007/s11689-010-9055-2.PubMedCentralPubMedCrossRef
6.
Frints S, Froyen G, Marynen P, Fryns J: X linked mental retardation: vanishing boundaries between non specific (MRX) and syndromic (MRXS) forms. Clin Genet. 2002, 62: 423-432. 10.1034/j.1399-0004.2002.620601.x.PubMedCrossRef
7.
Li H, Durbin R: Fast and accurate short read alignment with burrows–wheeler transform. Bioinformatics. 2009, 25: 1754-1760. 10.1093/bioinformatics/btp324.PubMedCentralPubMedCrossRef
8.
9.
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R: The sequence alignment/map format and SAMtools. Bioinformatics. 2009, 25: 2078-2079. 10.1093/bioinformatics/btp352.PubMedCentralPubMedCrossRef
10.
Wang K, Li M, Hakonarson H: ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010, 38: e164-10.1093/nar/gkq603.PubMedCentralPubMedCrossRef
11.
12.
Thisse C, Thisse B: High-resolution in situ hybridization to whole-mount zebrafish embryos. Nat Protocols. 2007, 3: 59-69.CrossRef
13.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods. 2010, 7: 248-249. 10.1038/nmeth0410-248.PubMedCentralPubMedCrossRef
14.
Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protocols. 2009, 4: 1073-1081. 10.1038/nprot.2009.86.CrossRef
15.
Masuda S, Das R, Cheng H, Hurt E, Dorman N, Reed R: Recruitment of the human TREX complex to mRNA during splicing. Genes Dev. 2005, 19: 1512-1517. 10.1101/gad.1302205.PubMedCentralPubMedCrossRef
16.
Rehwinkel J, Herold A, Gari K, Köcher T, Rode M, Ciccarelli FL, Wilm M, Izaurralde E: Genome-wide analysis of mRNAs regulated by the THO complex in Drosophila melanogaster. Nat Struct Mol Biol. 2004, 11: 558-566. 10.1038/nsmb759.PubMedCrossRef
17.
Sträßer K, Masuda S, Mason P, Pfannstiel J, Oppizzi M, Rodriguez-Navarro S, Rondón AG, Aguilera A, Struhl K, Reed R: TREX is a conserved complex coupling transcription with messenger RNA export. Nature. 2002, 417: 304-308. 10.1038/nature746.PubMedCrossRef
18.
Chávez S, Beilharz T, Rondón AG, Erdjument-Bromage H, Tempst P, Svejstrup JQ, Lithgow T, Aguilera A: A protein complex containing Tho2, Hpr1, Mft1 and a novel protein, Thp2, connects transcription elongation with mitotic recombination in Saccharomyces cerevisiae. EMBO J. 2000, 19: 5824-5834. 10.1093/emboj/19.21.5824.PubMedCentralPubMedCrossRef
19.
Rougemaille M, Dieppois G, Kisseleva-Romanova E, Gudipati RK, Lemoine S, Blugeon C, Boulay J, Jensen TH, Stutz F, Devaux F: THO/Sub2p functions to coordinate 3′-end processing with gene-nuclear pore association. Cell. 2008, 135: 308-321. 10.1016/j.cell.2008.08.005.PubMedCrossRef
20.
Jensen TH, Boulay J, Olesen JR, Colin J, Weyler M, Libri D: Modulation of transcription affects mRNP quality. Mol Cell. 2004, 16: 235-244. 10.1016/j.molcel.2004.09.019.PubMedCrossRef
21.
Jimeno S, García-Rubio M, Luna R, Aguilera A: A reduction in RNA polymerase II initiation rate suppresses hyper-recombination and transcription-elongation impairment of THO mutants. Mol Genet Genomics. 2008, 280: 327-336. 10.1007/s00438-008-0368-8.PubMedCrossRef
22.
Li Y, Wang X, Zhang X, Goodrich DW: Human hHpr1/p84/Thoc1 regulates transcriptional elongation and physically links RNA polymerase II and RNA processing factors. Mol Cell Biol. 2005, 25: 4023-4033. 10.1128/MCB.25.10.4023-4033.2005.PubMedCentralPubMedCrossRef
23.
Cheng H, Dufu K, Lee C-S, Hsu JL, Dias A, Reed R: Human mRNA export machinery recruited to the 5′ End of mRNA. Cell. 2006, 127: 1389-1400. 10.1016/j.cell.2006.10.044.PubMedCrossRef
24.
Katahira J, Inoue H, Hurt YY: Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. EMBO J. 2009, 28: 556-567. 10.1038/emboj.2009.5.PubMedCentralPubMedCrossRef
25.
El Bounkari O, Guria A, Klebba-Faerber S, Claußen M, Pieler T, Griffiths JR, Whetton AD, Koch A, Tamura T: Nuclear localization of the pre-mRNA associating protein THOC7 depends upon its direct interaction with Fms tyrosine kinase interacting protein (FMIP). FEBS Lett. 2009, 583: 13-18. 10.1016/j.febslet.2008.11.024.PubMedCrossRef
26.
Gasparri F, Sola F, Locatelli G, Muzio M: The death domain protein p84N5, but not the short isoform p84N5s, is cell cycle-regulated and shuttles between the nucleus and the cytoplasm. FEBS Lett. 2004, 574: 13-19. 10.1016/j.febslet.2004.07.074.PubMedCrossRef
27.
Dias AP, Dufu K, Lei H, Reed R: A role for TREX components in the release of spliced mRNA from nuclear speckle domains. Nat Comm. 2010, 1: 97-10.1038/ncomms1103.CrossRef
28.
Durfee T, Mancini MA, Jones D, Elledge SJ, Lee WH: The amino-terminal region of the retinoblastoma gene product binds a novel nuclear matrix protein that co-localizes to centers for RNA processing. J Cell Biol. 1994, 127: 609-622. 10.1083/jcb.127.3.609.PubMedCrossRef
29.
Chi B, Wang Q, Wu G, Tan M, Wang L, Shi M, Chang X, Cheng H: Aly and THO are required for assembly of the human TREX complex and association of TREX components with the spliced mRNA. Nucleic Acids Res. 2013, 41: 1294-1306. 10.1093/nar/gks1188.PubMedCentralPubMedCrossRef
30.
Poulton CJ, Schot R, Kia SK, Jones M, Verheijen FW, Venselaar H, deáWit MCY, deáGraaff E, Bertoli-Avella AM, Mancini GMS: Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am J Hum Genet. 2011, 89: 265-276. 10.1016/j.ajhg.2011.07.006.PubMedCentralPubMedCrossRef
31.
Roth KA, D’Sa C: Apoptosis and brain development. Ment Retard Dev D R. 2001, 7: 261-266. 10.1002/mrdd.1036.CrossRef
32.
O’Driscoll M, Jeggo PA: The role of the DNA damage response pathways in brain development and microcephaly: insight from human disorders. DNA Repair. 2008, 7: 1039-1050. 10.1016/j.dnarep.2008.03.018.PubMedCrossRef
33.
Li Y, Lin AW, Zhang X, Wang Y, Wang X, Goodrich DW: Cancer cells and normal cells differ in their requirements for Thoc1. Cancer Res. 2007, 67: 6657-6664. 10.1158/0008-5472.CAN-06-3234.PubMedCentralPubMedCrossRef
34.
Mancini A, Niemann-Seyde SC, Pankow R, El Bounkari O, Klebba-Färber S, Koch A, Jaworska E, Spooncer E, Gruber AD, Whetton AD, Tamura T: THOC5/FMIP, an mRNA export TREX complex protein, is essential for hematopoietic primitive cell survival in vivo. BMC Biol. 2010, 8: 1-10.1186/1741-7007-8-1.PubMedCentralPubMedCrossRef
35.
Bhalla K, Luo Y, Buchan T, Beachem MA, Guzauskas GF, Ladd S, Bratcher SJ, Schroer RJ, Balsamo J, DuPont BR: Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. Am J Hum Genet. 2008, 83: 703-713. 10.1016/j.ajhg.2008.10.020.PubMedCentralPubMedCrossRef
36.
37.
Ropers HH: Genetics of early onset cognitive impairment. Ann Rev of Genomics Hum Genet. 2010, 11: 161-187. 10.1146/annurev-genom-082509-141640.CrossRef
38.
Ramakers GJA: Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci. 2002, 25: 191-199. 10.1016/S0166-2236(00)02118-4.PubMedCrossRef
39.
Mir A, Kaufman L, Noor A, Motazacker MM, Jamil T, Azam M, Kahrizi K, Rafiq MA, Weksberg R, Nasr T: Identification of mutations in TRAPPC9, which encodes the NIK-and IKK-[beta]-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet. 2009, 85: 909-915. 10.1016/j.ajhg.2009.11.009.PubMedCentralPubMedCrossRef
40.
Mochida GH, Mahajnah M, Hill AD, Basel-Vanagaite L, Gleason D, Hill RS, Bodell A, Crosier M, Straussberg R, Walsh CA: A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am J Hum Genet. 2009, 85: 897-902. 10.1016/j.ajhg.2009.10.027.PubMedCentralPubMedCrossRef
41.
Philippe O, Rio M, Carioux A, Plaza JM, Guigue P, Molinari F, Boddaert N, Bole-Feysot C, Nitschke P, Smahi A: Combination of linkage mapping and microarray-expression analysis identifies NF-[kappa] B signaling defect as a cause of autosomal-recessive mental retardation. Am J Hum Genet. 2009, 85: 903-908. 10.1016/j.ajhg.2009.11.007.PubMedCentralPubMedCrossRef
42.
Kaindl AM, Passemard S, Kumar P, Kraemer N, Issa L, Zwirner A: Many roads lead to primary autosomal recessive microcephaly. Prog Neurobiol. 2010, 90: 363-383. 10.1016/j.pneurobio.2009.11.002.PubMedCrossRef
43.
Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T, Vernay B, Al Sanna N, Saggar A, Hamel B, Earnshaw WC: Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genetics. 2007, 40: 232-236.CrossRef
44.
Raymond F: Monogenic causes of mental retardation. Monogr Hum Genet. 2010, 18: 89-100.CrossRef
45.
Pak CH, Garshasbi M, Kahrizi K, Gross C, Apponi LH, Noto JJ, Kelly SM, Leung SW, Tzschach A, Behjati F: Mutation of the conserved polyadenosine RNA binding protein, ZC3H14/dNab2, impairs neural function in drosophila and humans. PNAS. 2011, 108: 12390-12395. 10.1073/pnas.1107103108.PubMedCentralPubMedCrossRef
Metadata
Title
Intellectual disability associated with a homozygous missense mutation in THOC6
Authors
Chandree L Beaulieu
Lijia Huang
A Micheil Innes
Marie-Andree Akimenko
Erik G Puffenberger
Charles Schwartz
Paul Jerry
Carole Ober
Robert A Hegele
D Ross McLeod
Jeremy Schwartzentruber
Jacek Majewski
Dennis E Bulman
Jillian S Parboosingh
Kym M Boycott
FORGE Canada Consortium
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2013
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/1750-1172-8-62

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