Deletion of REXO1L1 locus in a patient with malabsorption syndrome, growth retardation, and dysmorphic features: a novel recognizable microdeletion syndrome?

BMC Medical Genetics

Francesco Pallone²  Giuseppe Novelli⁴  Federica Sangiuolo⁶  Marina Frontali⁸  Caterina Tanzarella¹  Livia Biancone²  Emma Calabrese²  Giampiero Palmieri⁵  Anna Maria Nardone⁹  Barbara Testa⁶  Daniela Minella⁶  Norma Licata³  Francesca Gullotta⁶  Antonio Antoccia¹  Michela Biancolella⁶  Alessandra di Masi¹  Antonio Novelli⁷  Maria Rosaria D’Apice⁹ 

[1] Department of Biology, “Roma Tre” University, Rome, Italy;Department of Internal Medicine, Gastrointestinal Unit, Tor Vergata University of Rome, Rome, Italy;Department of Neuroscience, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy;San Pietro Fatebenefratelli Hospital, Rome, Italy;Pathological Anatomy Unit, University Tor Vergata, Rome, Italy;Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy;Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy;Institute of Translational Pharmacology, Rome, CNR, Italy;Fondazione Policlinico Tor Vergata, Rome, Italy

关键词: Inflammation and apoptosis of gastrointestinal mucosa;    Facial dysmorphisms;    CNV;    aCGH;    REXO1L1 gene;    8q21.2 microdeletion;   

Others  :  1177685
DOI  :  10.1186/s12881-015-0164-3

 received in 2014-09-10, accepted in 2015-03-12,  发布年份 2015

【 摘 要 】

Background

Copy number variations (CNVs) can contribute to genetic variation among individuals and/or have a significant influence in causing diseases. Many studies consider new CNVs’ effects on protein family evolution giving rise to gene duplicates or losses. “Unsuccessful” duplicates that remain in the genome as pseudogenes often exhibit functional roles. So, changes in gene and pseudogene number may contribute to development or act as susceptibility alleles of diseases.

Case presentation

We report a de novo heterozygous 271 Kb microdeletion at 8q21.2 region which includes the family of REXO1L genes and pseudogenes in a young man affected by global development delay, progeroid signs, and gastrointestinal anomalies. Molecular and cellular analysis showed that the REXO1L1 gene hemizygosity in a patient’s fibroblasts induces genetic instability and increased apoptosis after treatment with different DNA damage-induced agents.

Conclusions

The present results support the hypothesis that low copy gene number within REXO1L1 cluster could play a significant role in this complex clinical and cellular phenotype.

【 授权许可】

   
2015 D'Apice et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Shen Y, Wu BL: Microarray-based genomic DNA profiling technologies in clinical molecular diagnostics. Clin Chem 2009, 55:659-69.
• [2]Shinawi M, Cheung SW: The array CGH and its clinical applications. Drug Discov Today 2008, 13:760-70.
• [3]Klopocki E, Mundlos S: Copy-number variations, noncoding sequences, and human phenotypes. Annu Rev Genomics Hum Genet 2011, 12:53-72.
• [4]Zhang F, Gu W, Hurles ME, Lupski JR: Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 2009, 10:451-81.
• [5]Weise A, Mrasek K, Klein E, Mulatinho M, Llerena JC Jr, Hardekopf D, et al.: Microdeletion and microduplication syndromes. J Histochem Cytochem 2012, 60:346-58.
• [6]Dzirlo L, Blaha B, Müller C, Hubner M, Kneussl M, Huber K, et al.: Capsule endoscopic appearance of the small-intestinal mucosa in Whipple’s disease and the changes that occur during antibiotic therapy. Endoscopy 2007, 39(suppl 1):E207-8.
• [7]Ladas SD, Triantafyllou K, Spada C, Riccioni ME, Rey JF, Niv Y, et al.: ESGE clinical guidelines committee, European society of gastrointestinal endoscopy (ESGE): recommendations on clinical use of video capsule endoscopy to investigate small-bowel, esophageal and colonic diseases. Endoscopy 2010, 42:220-7.
• [8]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001, 25:402-8.
• [9]Feuk L, Carson AR, Scherer SW: Structural variation in the human genome. Nat Rev Genet 2006, 7:85-97.
• [10]Sneddon TP, Church DM: Online resources for genomic structural variation. Methods Mol Biol 2012, 838:273-89.
• [11]Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, et al.: Detection of large-scale variation in the human genome. Nat Genet 2004, 36:949-51.
• [12]Balciuniene J, Feng N, Iyadurai K, Hirsch B, Charnas L, Bill BR, et al.: Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am J Hum Genet 2007, 80:938-47.
• [13]Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, et al.: Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 2005, 77:78-88.
• [14]Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, et al.: Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006, 38:1038-42.
• [15]Krepischi-Santos ACV, Vianna-Morgante AM, Jehee FS, Passos-Bueno MR, Knijnenburg J, Szuhai K, et al.: Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndromes revisited and new alterations. Cytogenet Genome Res 2006, 115:254-61.
• [16]Lee C, Iafrate AJ, Brothman AR: Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet 2007, 39:548-54.
• [17]Rodriguez V, Chen Y, Elkahloun A, Dutra A, Pak E, Chandrasekharappa S: Chromosome 8 BAC array comparative genomic hybridization and expression analysis identify amplification and overexpression of TRMT12 in breast cancer. Genes, Chromosomes & Cancer 2007, 46:694-707.
• [18]Korbel JO, Kim PM, Chen X, Urban AE, Weissman S, Snyder M, et al.: The current excitement about copy-number variation: how it relates to gene duplication and protein families. Curr Opin Struct Biol 2008, 18:366-74.
• [19]Harrison PM, Gerstein M: Studying genomes through the aeons: protein families, pseudogenes and proteome evolution. J Mol Biol 2002, 318:1155-74.
• [20]Balakirev ES, Ayala F: Pseudogenes: are they “Junk” or functional DNA? Annu Rev Genet 2003, 37:123-51.
• [21]Barøy T, Misceo D, Frengen E: Structural variation in the human genome contributes to variation of traits. Tidsskr Nor Laegeforen 2008, 128:1951-5.
• [22]Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, et al.: The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005, 307:1434-40.
• [23]Wain LV, Armour JA, Tobin MD: Genomic copy number variation, human health, and disease. Lancet 2009, 374:340-50.
• [24]Koike R, Iizuka T, Watanabe T, Miyasaka N: The GOR gene product cannot cross-react with hepatitis C virus in humans. Clin Exp Immunol 2001, 124:429-34.
• [25]Li Z, Deutscher MP: The role of individual exoribonucleases in processing at the 3′ end of Escherichia coli tRNA precursors. J Biol Chem 1994, 269:6064-71.
• [26]Li Z, Pandit S, Deutscher MP: 3′ exoribonucleolytic trimming is a common feature of the maturation of small, stable RNAs in Escherichia coli. Proc Natl Acad Sci U S A 1998, 95:2856-61.
• [27]Ghosh S, Deutscher MP: Oligoribonuclease is an essential component of the mRNA decay pathway. Proc Natl Acad Sci U S A 1999, 96:4372-7.
• [28]Briggs MW, Burkard KT, Butler JS: Rrp6p, the yeast homologue of the human PM-Scl 100-kDa autoantigen, is essential for efficient 5.8 S rRNA 3′ end formation. J Biol Chem 1998, 273:13255-63.
• [29]van Hoof A, Lennertz P, Parker R: Three conserved members of the RNase D family have unique and overlapping functions in the processing of 5S, 5.8S, U4, U5, RNase MRP and RNase P RNAs in yeast. EMBO J 2000, 19:1357-65.
• [30]van Hoof A, Lennertz P, Parker R: Yeast exosome mutants accumulate 3′-extended polyadenylated forms of U4 small nuclear RNA and small nucleolar RNAs. Mol Cell Biol 2000, 20:441-52.
• [31]Moser MJ, Holley WR, Chatterjee A, Mian IS: The proofreading domain of Escherichia coli DNA polymerase I and other DNA and/or RNA exonuclease domains. Nucleic Acids Res 1997, 25:5110-8.
• [32]Espert L, Degols G, Gongora C, Blondel D, Williams BR, Silverman RH, et al.: ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses. J Biol Chem 2003, 278:16151-89.
• [33]Yang XC, Purdy M, Marzluff WF, Dominski Z: Characterization of 3′ hExo, a 3′ exonuclease specifically interacting with the 3′ end of histone mRNA. J Biol Chem 2006, 281:30447-54.
• [34]Nguyen LH, Erzberger JP, Root J, Wilson DM III: The human homolog of Escherichia coli Orn degrades small single-stranded RNA and DNA oligomers. J Biol Chem 2000, 275:25900-6.
• [35]Hao Y, Yang D: Cloning, eukaryotic expression of human ISG20 and preliminary study on the effect of its anti-HBV. J Huazhong Univ Sci Technolog Med Sci 2008, 28:11-3.
• [36]Datta K, Niyogi K: A novel oligoribonuclease of Escherichia coli. II Mechanism of action J Biol Chem 1975, 250:7313-9.
• [37]Mechold U, Ogryzko V, Ngo S, Danchin A: Oligoribonuclease is a common downstream target of lithium-induced pAp accumulation in Escherichia coli and human cells. Nucleic Acids Res 2006, 34:2364-73.
• [38]Fałkowska-Podstawka M, Wernicki A: Heat shock proteins in health and disease. Pol J Vet Sci 2003, 6:61-70.
• [39]Natarajan AT, Obe G: Molecular mechanisms involved in the production of chromosomal aberrations I. Utilization of Neurospora endonuclease for the study of aberration production in G2 stage of the cell cycle. Mutat Res 1978, 52:137-49.