Dystonia, facial dysmorphism, intellectual disability and breast cancer associated with a chromosome 13q34 duplication and overexpression of TFDP1: case report

BMC Medical Genetics

Michael S Okun²  Kelly D Foote²  Ramon L Rodriguez³  Satya R Vemula¹  Garrett L Rampon¹  Jianfeng Xiao¹  Mark S LeDoux¹  Mariana Moscovich³ 

[1] Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Suite 415 Link Building, Memphis, Tennessee 38163, USA;Center for Movement Disorders & Neurorestoration, Department of Neurosurgery, University of Florida, McKnight Brain Institute, 100 S Newell Drive, Room L2-100, Gainesville, FL 32610, USA;Center for Movement Disorders and Neurorestoration, Department of Neurology, University of Florida College of Medicine, 100 S Newell Drive, Room L3-101, Gainesville, FL 32610, USA

关键词: G₁-S Checkpoint pathway;    Breast cancer;    TFDP1;    Duplication;    Chromosome 13q34;    Dystonia;   

Others  :  1127706
DOI  :  10.1186/1471-2350-14-70

 received in 2012-09-07, accepted in 2013-07-03,  发布年份 2013

【 摘 要 】

Background

Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G₁-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored.

Case presentation

Cytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2.

Conclusion

Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.

【 授权许可】

   
2013 Moscovich et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Castillo SD, Angulo B, Suarez-Gauthier A, Melchor L, Medina PP, Sanchez-Verde L, Torres-Lanzas J, Pita G, Benitez J, Sanchez-Cespedes M: Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer. J Pathol 2010, 222(1):89-98.
• [2]Diosdado B, Buffart TE, Watkins R, Carvalho B, Ylstra B, Tijssen M, Bolijn AS, Lewis F, Maude K, Verbeke C, et al.: High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas. Clin Cancer Res 2010, 16(5):1391-1401.
• [3]Yasui K, Arii S, Zhao C, Imoto I, Ueda M, Nagai H, Emi M, Inazawa J: TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas. Hepatol 2002, 35(6):1476-1484.
• [4]Shinomiya T, Mori T, Ariyama Y, Sakabe T, Fukuda Y, Murakami Y, Nakamura Y, Inazawa J: Comparative genomic hybridization of squamous cell carcinoma of the esophagus: the possible involvement of the DPI gene in the 13q34 amplicon. Genes Chromosomes Cancer 1999, 24(4):337-344.
• [5]Abba MC, Fabris VT, Hu Y, Kittrell FS, Cai WW, Donehower LA, Sahin A, Medina D, Aldaz CM: Identification of novel amplification gene targets in mouse and human breast cancer at a syntenic cluster mapping to mouse ch8A1 and human ch13q34. Cancer Res 2007, 67(9):4104-4112.
• [6]Melchor L, Saucedo-Cuevas LP, Munoz-Repeto I, Rodriguez-Pinilla SM, Honrado E, Campoverde A, Palacios J, Nathanson KL, Garcia MJ, Benitez J: Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes. Breast Cancer Res 2009, 11(6):R86. BioMed Central Full Text
• [7]Lomazzi M, Moroni MC, Jensen MR, Frittoli E, Helin K: Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry. Nat Genet 2002, 31(2):190-194.
• [8]Ravitz MJ, Wenner CE: Cyclin-dependent kinase regulation during G1 phase and cell cycle regulation by TGF-beta. Adv Cancer Res 1997, 71:165-207.
• [9]Talluri S, Isaac CE, Ahmad M, Henley SA, Francis SM, Martens AL, Bremner R, Dick FA: A G1 checkpoint mediated by the retinoblastoma protein that is dispensable in terminal differentiation but essential for senescence. Mol Cell Biol 2010, 30(4):948-960.
• [10]Hoche F, Seidel K, Theis M, Vlaho S, Schubert R, Zielen S, Kieslich M: Neurodegeneration in ataxia telangiectasia: what is new? What is evident? Neuropediatrics 2012, 43(3):119-129.
• [11]Saunders-Pullman R, Raymond D, Stoessl AJ, Hobson D, Nakamura K, Pullman S, Lefton D, Okun MS, Uitti R, Sachdev R, et al.: Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurol 2012, 78(9):649-657.
• [12]Xiao J, Uitti RJ, Zhao Y, Vemula SR, Perlmutter JS, Wszolek ZK, Maraganore DM, Auburger G, Leube B, Lehnhoff K, et al.: Mutations in CIZ1 cause adult onset primary cervical dystonia. Ann Neurol 2012, 71(4):458-469.
• [13]Swift M, Lukin JL: Breast cancer incidence and the effect of cigarette smoking in heterozygous carriers of mutations in the ataxia-telangiectasia gene. Cancer Epidemiol Biomarkers Prev 2008, 17(11):3188-3192.
• [14]Cheng Q, Chen L, Li Z, Lane WS, Chen J: ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J 2009, 28(24):3857-3867.
• [15]Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K, Goto S, Matsumoto S, Tabuena MD, Maranon E, Dantes M, et al.: Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 2007, 80(3):393-406.
• [16]Li HH, Li AG, Sheppard HM, Liu X: Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression. Mol Cell 2004, 13(6):867-878.
• [17]Coverley D, Marr J, Ainscough J: Ciz1 promotes mammalian DNA replication. J Cell Sci 2005, 118(Pt 1):101-112.
• [18]Koh YH, Rehfeld K, Ganetzky B: A Drosophila model of early onset torsion dystonia suggests impairment in TGF-beta signaling. Hum Mol Genet 2004, 13(18):2019-2030.
• [19]Cayrol C, Lacroix C, Mathe C, Ecochard V, Ceribelli M, Loreau E, Lazar V, Dessen P, Mantovani R, Aguilar L, et al.: The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes. Blood 2007, 109(2):584-594.
• [20]Xiao J, Zhao Y, Bastian RW, Perlmutter JS, Racette BA, Tabbal SD, Karimi M, Paniello RC, Wszolek ZK, Uitti RJ, et al.: Novel THAP1 sequence variants in primary dystonia. Neurol 2010, 74(3):229-238.
• [21]Liu X, Jian X, Boerwinkle E: dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat 2011, 32(8):894-899.
• [22]Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, et al.: Clustal W and Clustal X version 2.0. Bioinformatics 2007, 23(21):2947-2948.
• [23]Vemula SR, Puschmann A, Xiao J, Zhao Y, Rudzinska M, Frei KP, Truong DD, Wszolek ZK, LeDoux MS: Role of Gα(olf) in familial and sporadic adult-onset primary dystonia. Hum Mol Genet 2013, 22(12):2510-2519.
• [24]Ng PC, Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 2003, 31(13):3812-3814.
• [25]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(4):248-249.
• [26]Schwarz JM, Rödelsperger C, Schuelke M, Seelow D: MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010, 7(8):575-576.
• [27]Nicoloso MS, Sun H, Spizzo R, Kim H, Wickramasinghe P, Shimizu M, Wojcik SE, Ferdin J, Kunej T, Xiao L, et al.: Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res 2010, 70(7):2789-2798.
• [28]Silva SN, Tomar M, Paulo C, Gomes BC, Azevedo AP, Teixeira V, Pina JE, Rueff J, Gaspar JF: Breast cancer risk and common single nucleotide polymorphisms in homologous recombination DNA repair pathway genes XRCC2, XRCC3, NBS1 and RAD51. Cancer Epidemiol 2010, 34(1):85-92.
• [29]LeDoux MS: The genetics of dystonias. Adv Genet 2012, 79:35-85.
• [30]Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, de Leon D, Brin MF, Raymond D, Corey DP, et al.: The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 1997, 17(1):40-48.
• [31]Charlesworth G, Plagnol V, Holmström KM, Bras J, Sheerin UM, Preza E, Rubio-Agusti I, Ryten M, Schneider SA, Stamelou M, et al.: Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am J Hum Genet 2012, 91(6):1041-1050.
• [32]Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, Lang AE, Liang TW, Trosch RM, et al.: Mutations in GNAL cause primary torsion dystonia. Nat Genet 2013, 45(1):88-92.
• [33]Hersheson J, Mencacci NE, Davis M, Macdonald N, Trabzuni D, Ryten M, Pittman A, Paudel R, Kara E, Fawcett K, et al.: Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia. Ann Neurol 2012. Dec 13. [Epub ahead of print] PubMed PMID: 23424103
• [34]Burke RE, Fahn S, Jankovic J, Marsden CD, Lang AE, Gollomp S, Ilson J: Tardive dystonia: late-onset and persistent dystonia caused by antipsychotic drugs. Neurol 1982, 32(12):1335-1346.
• [35]Calakos N, Patel VD, Gottron M, Wang G, Tran-Viet KN, Brewington D, Beyer JL, Steffens DC, Krishnan RR, Zuchner S: Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia. J Med Genet 2010, 47(9):646-650.
• [36]Lee HJ, Kang SG: Genetics of tardive dyskinesia. Int Rev Neurobiol 2011, 98:231-264.
• [37]Cohen OS, Hassin-Baer S, Spiegelmann R: Deep brain stimulation of the internal globus pallidus for refractory tardive dystonia. Parkinsonism Relat Disord 2007, 13(8):541-544.
• [38]Krauss JK: Deep brain stimulation for dystonia in adults. Overview and developments. Stereotact Funct Neurosurg 2002, 78(3–4):168-182.
• [39]Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Benabid AL, Cornu P, Lagrange C, Tezenas Du Montcel S, Dormont D, Grand S, et al.: Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005, 352(5):459-467.
• [40]Kupsch A, Benecke R, Muller J, Trottenberg T, Schneider GH, Poewe W, Eisner W, Wolters A, Muller JU, Deuschl G, et al.: Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006, 355(19):1978-1990.
• [41]Isaias IU, Alterman RL, Tagliati M: Outcome predictors of pallidal stimulation in patients with primary dystonia: the role of disease duration. Brain 2008, 131(Pt 7):1895-1902.
• [42]Tagliati M, Shils J, Sun C, Alterman R: Deep brain stimulation for dystonia. Expert Rev Med Devices 2004, 1(1):33-41.
• [43]Hong X, Tsai HJ, Liu X, Li Z, Tang G, Xing H, Yang J, Wang B, Feng Y, Xu X, et al.: A large-scale genome-wide linkage analysis to map loci linked to stature in Chinese population. J Clin Endocrinol Metab 2008, 93(11):4511-4518.
• [44]Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, et al.: Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 2008, 359(16):1685-1699.
• [45]Girirajan S, Eichler EE: Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet 2010, 19(R2):R176-R187.
• [46]Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH, Shafer N, Bernier R, Ferrero GB, Silengo M, et al.: Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genet 2011, 7(11):e1002334.
• [47]Rosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG: Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med 2012. Dec 20. [Epub ahead of print] PubMed PMID: 23258348
• [48]Hippisley-Cox J, Vinogradova Y, Coupland C, Parker C: Risk of malignancy in patients with schizophrenia or bipolar disorder: nested case–control study. Arch Gen Psychiatry 2007, 64(12):1368-1376.
• [49]Chen LL, Carmichael GG: Decoding the function of nuclear long non-coding RNAs. Curr Opin Cell Biol 2010, 22(3):357-364.
• [50]Shen C, Huang Y, Liu Y, Wang G, Zhao Y, Wang Z, Teng M, Wang Y, Flockhart DA, Skaar TC, et al.: A modulated empirical Bayes model for identifying topological and temporal estrogen receptor alpha regulatory networks in breast cancer. BMC Syst Biol 2011, 5:67. BioMed Central Full Text
• [51]Tian Y, Stamova B, Jickling GC, Liu D, Ander BP, Bushnell C, Zhan X, Davis RR, Verro P, Pevec WC, et al.: Effects of gender on gene expression in the blood of ischemic stroke patients. J Cereb Blood Flow Metab 2012, 32(5):780-791.