Indian Journal of Human Genetics
Home Current Issue Archives Guidelines Subscriptions e-Alerts Login 
Users online: 23
Print this page  Email this page Small font sizeDefault font sizeIncrease font size


 
            Table of Contents  
LETTER TO THE EDITOR
Year : 2013  |  Volume : 19  |  Issue : 2  |  Page : 274-275
 

Effect of the novel Moroccan BRCA1 and BRCA2 frameshift mutations


1 Genetics and Molecular Pathology Laboratory, Medical School of Casablanca, Morocco
2 Department of Oncology, Ibn Rochd University Hospital of Casablanca, Morocco

Date of Web Publication5-Aug-2013

Correspondence Address:
Sellama Nadifi
Genetics and Molecular Pathology Laboratory, Medical School of Casablanca
Morocco
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-6866.116114

Get Permissions

 



How to cite this article:
Tazzite A, Jouhadi H, Hamzi K, Benider A, Nadifi S. Effect of the novel Moroccan BRCA1 and BRCA2 frameshift mutations. Indian J Hum Genet 2013;19:274-5

How to cite this URL:
Tazzite A, Jouhadi H, Hamzi K, Benider A, Nadifi S. Effect of the novel Moroccan BRCA1 and BRCA2 frameshift mutations. Indian J Hum Genet [serial online] 2013 [cited 2016 May 24];19:274-5. Available from: http://www.ijhg.com/text.asp?2013/19/2/274/116114


Sir,

Deleterious BReast CAncer susceptibility gene 1 (BRCA1) and BReast CAncer susceptibility gene 2 (BRCA2) mutations have significant clinical implications. Point mutations in essential functional domains and frameshift mutations resulting in early termination of protein translation were associated with high breast and ovarian cancer risk. Indeed, premature stop codons destabilize mRNA and lead to a state of haplo-insufficiency. [1] During our BRCA1/2 mutation screening in Moroccan patients, we have identified four novel germline mutations. [2] The c.2805delA BRCA1 mutation generates a dysfunctional truncated protein as a result of the introduction of a premature stop codon at position 999. This mutation occurs within the largest exon 11 of BRCA1 gene which encodes two putative nuclear localization signals (NLSs) [3],[4] for targeting BRCA1 to the nucleus. It also contains a domain that interacts with the DNA repair protein (RAD51). [5],[6],[7] Many other proteins interact directly or indirectly with BRCA1 exon 11 including c-Myc, RB, JunB, FANCA, RAD50, p53, and BRCA2. [8],[9] On the other hand, the stop codon at position 999 would generate a truncated protein that lack the BRCT domain, a high conserved region which is involved in protein-protein interaction and facilitate the formation of hetero- and homo-oligomers. [10] Consequently, the BRCT motifs of BRCA1 bind to the phosphorylated protein partners involved in the control of the G2/M phase checkpoint and DNA damage repair. [11],[12] Truncation and missense mutations in this region correlate with a high-risk for breast and ovarian cancers. [13],[14]

Furthermore, three novel BRCA2 frameshift mutations were identified (c.3381delT, c.7110delA and c. 7235insG). They lead to protein truncation at amino acid positions 1150, 2376, and 2413 respectively. The c.7110delA and c.7235insG mutations were located in exon 14 while c.3381delT mutation was detected in exon 11 which codes for a large central region of the protein and houses eight highly conserved BRC repeats reported to have an important ability to bind RAD51 an essential enzyme for homologous DNA recombination. It was shown that deletion of several BRC repeats in mice leads to cancer development [15] and somatic mutations in these repeats have been found to be associated with breast cancer. [16] Thus, mutations within these repeats are associated with an increased cancer predisposition risk. [17],[18],[19] Moreover, these BRCA2 truncated mutations cause loss of C-terminal region that contains DNA-binding domain (DBD) implicated in cell cycle checkpoints [20] and two putative NLSs. Loss of these NLSs, through truncations, makes protein cytoplasmic since it cannot perform a translocation into the nucleus. [21]

Otherwise, the identification of new mutations in the Moroccan population suggests that it still presents a fertile field for advanced research and extensive studies in this area.

 
   References Top

1.Chen X, Truong TT, Weaver J, Bove BA, Cattie K, Armstrong BA, et al. Intronic alterations in BRCA1 and BRCA2: Effect on mRNA splicing fidelity and expression. Hum Mutat 2006;27:427-35.  Back to cited text no. 1
[PUBMED]    
2.Tazzite A, Jouhadi H, Nadifi S, Aretini P, Falaschi E, Collavoli A, Benider A, Caligo MA. BRCA1 and BRCA2 germline mutations in Moroccan breast/ovarian cancer families: Novel mutations and unclassified variants. Gynecol Oncol 2012;125:687-92.  Back to cited text no. 2
[PUBMED]    
3.Chen CF, Li S, Chen Y, Chen PL, Sharp ZD, Lee WH. The nuclear localization sequences of the BRCA1 protein interact with the importin-alpha subunit of the nuclear transport signal receptor. J Biol Chem 1996;271:32863-8.  Back to cited text no. 3
[PUBMED]    
4.Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH. BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res 1996;56:3168-72.  Back to cited text no. 4
[PUBMED]    
5.Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 1997;88:265-75.  Back to cited text no. 5
[PUBMED]    
6.Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 1997;90:425-35.  Back to cited text no. 6
[PUBMED]    
7.Shinohara A, Ogawa H, Ogawa T. Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein. Cell 1992;69:457-70.  Back to cited text no. 7
[PUBMED]    
8.Rosen EM, Fan S, Pestell RG, Goldberg ID. BRCA1 gene in breast cancer. J Cell Physiol 2003;196:19-41.  Back to cited text no. 8
[PUBMED]    
9.Boulton SJ. Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans 2006;34:633-45.  Back to cited text no. 9
[PUBMED]    
10.Watts FZ, Brissett NC. Linking up and interacting with BRCT domains. DNA Repair (Amst) 2010;9:103-8.  Back to cited text no. 10
[PUBMED]    
11.Varma AK, Brown RS, Birrane G, Ladias JA. Structural basis for cell cycle checkpoint control by the BRCA1-CtIP complex. Biochemistry 2005;44:10941-6.  Back to cited text no. 11
[PUBMED]    
12.Williams RS, Lee MS, Hau DD, Glover JN. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nat Struct Mol Biol 2004;11:519-25.  Back to cited text no. 12
[PUBMED]    
13.Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 1994;266:120-2.  Back to cited text no. 13
[PUBMED]    
14.Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71.  Back to cited text no. 14
[PUBMED]    
15.Donoho G, Brenneman MA, Cui TX, Donoviel D, Vogel H, Goodwin EH, et al. Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice. Genes Chromosomes Cancer 2003;36:317-31.  Back to cited text no. 15
[PUBMED]    
16.Chen FM, Hou MF, Chang MY, Wang JY, Hsieh JS, Ou-Yang F, et al. High frequency of somatic missense mutation of BRCA2 in female breast cancer from Taiwan. Cancer Lett 2005;220:177-84.  Back to cited text no. 16
[PUBMED]    
17.San Filippo J, Chi P, Sehorn MG, Etchin J, Krejci L, Sung P. Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide. J Biol Chem 2006;281:11649-57.  Back to cited text no. 17
    
18.Galkin VE, Esashi F, Yu X, Yang S, West SC, Egelman EH. BRCA2 BRC motifs bind RAD51-DNA filaments. Proc Natl Acad Sci U S A 2005;102:8537-42.  Back to cited text no. 18
[PUBMED]    
19.Shivji MK, Davies OR, Savill JM, Bates DL, Pellegrini L, Venkitaraman AR. A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange. Nucleic Acids Res 2006;34:4000-11.  Back to cited text no. 19
[PUBMED]    
20.Daniels MJ, Wang Y, Lee M, Venkitaraman AR. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 2004;306:876-9.  Back to cited text no. 20
[PUBMED]    
21.Spain BH, Larson CJ, Shihabuddin LS, Gage FH, Verma IM. Truncated BRCA2 is cytoplasmic: Implications for cancer-linked mutations. Proc Natl Acad Sci USA 1999;96:13920-5.  Back to cited text no. 21
[PUBMED]    




 

Top
Print this article  Email this article
           

    

 
   Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Article in PDF (210 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    References

 Article Access Statistics
    Viewed549    
    Printed9    
    Emailed0    
    PDF Downloaded19    
    Comments [Add]    

Recommend this journal