Abstract
The clinical phenotype of patients with ring chromosomes usually reflects the loss of genomic material during ring formation. However, phenotypic alterations can also be found in the presence of complete ring chromosomes, in which the breakage and rejoining in terminal regions of both chromosome arms result in no gene loss. Here, we present a patient with a ring chromosome 14 that lost nothing but the telomeres. Since he and other patients with a similar chromosome abnormality present certain abnormal characteristics, we investigated the gene expression of eight chromosome 14 genes to find out whether the configuration of the ring had changed it, possibly producing some of these clinical features. The expression of these eight genes was studied by quantitative real-time polymerase chain reaction (qPCR) in the patient and in seven controls matched for gender and age. Two of them were found to be downregulated in the patient compared to the controls, indicating that his phenotype might be related to alterations in the expression of genes located in the abnormal chromosome, even when the copy number is normal. Thus, the phenotypic alterations found in the presence of complete ring chromosomes may be related to changes in the chromatin architecture, bringing about a change of expression by position effect. These results may explain some of the characteristics presented by our patient.
Similar content being viewed by others
References
Benko S, Fantes JA, Amiel J, Kleinjan DJ, Thomas S, Ramsay J, Jamshidi N, Essafi A, Heaney S, Gordon CT, McBride D, Golzio C, Fisher M, Perry P, Abadie V, Ayuso C, Holder-Espinasse M, Kilpatrick N, Lees MM, Picard A, Temple IK, Thomas P, Vazquez MP, Vekemans M, Roest Crollius H, Hastie ND, Munnich A, Etchevers HC, Pelet A, Farlie PG, Fitzpatrick DR, Lyonnet S (2009) Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence. Nat Genet 41(3):359–364
Brock GJ, Charlton J, Bird A (1999) Densely methylated sequences that are preferentially localized at telomere-proximal regions of human chromosomes. Gene 240(2):269–277
Castermans D, Thienpont B, Volders K, Crepel A, Vermeesch JR, Schrander-Stumpel CT, Van de Ven WJ, Steyaert JG, Creemers JW, Devriendt K (2008) Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism. Eur J Hum Genet 16(10):1187–1192
Egecioglu D, Brickner JH (2011) Gene positioning and expression. Curr Opin Cell Biol 23(3):338–345
Feuk L (2012) Genomic structural variants: methods and protocols. Humana Press, New York, 386 pp
Finelli P, Sirchia SM, Masciadri M, Crippa M, Recalcati MP, Rusconi D, Giardino D, Monti L, Cogliati F, Faravelli F, Natacci F, Zoccante L, Bernardina BD, Russo S, Larizza L (2012) Juxtaposition of heterochromatic and euchromatic regions by chromosomal translocation mediates a heterochromatic long-range position effect associated with a severe neurological phenotype. Mol Cytogenet 5:16
Guilherme RS, de Freitas Ayres Meloni V, Sodré CP, Christofolini DM, Pellegrino R, de Mello CB, Conlin LK, Hutchinson AL, Spinner NB, Brunoni D, Kulikowski LD, Melaragno MI (2010) Cytogenetic and molecular evaluation and 20-year follow-up of a patient with ring chromosome 14. Am J Med Genet A 152A(11):2865–2869
Guilherme RS, Meloni VF, Kim CA, Pellegrino R, Takeno SS, Spinner NB, Conlin LK, Christofolini DM, Kulikowski LD, Melaragno MI (2011) Mechanisms of ring chromosome formation, ring instability and clinical consequences. BMC Med Genet 12:171
Harewood L, Liu M, Keeling J, Howatson A, Whiteford M, Branney P, Evans M, Fantes J, Fitzpatrick DR (2010) Bilateral renal agenesis/hypoplasia/dysplasia (BRAHD): postmortem analysis of 45 cases with breakpoint mapping of two de novo translocations. PLoS One 5(8):e12375
Howard PJ, Clark D, Dearlove J (1988) Retinal/macular pigmentation in conjunction with ring 14 chromosome. Hum Genet 80(2):140–142
Kleinjan DJ, van Heyningen V (1998) Position effect in human genetic disease. Hum Mol Genet 7(10):1611–1618
Knijnenburg J, van Haeringen A, Hansson KB, Lankester A, Smit MJ, Belfroid RD, Bakker E, Rosenberg C, Tanke HJ, Szuhai K (2007) Ring chromosome formation as a novel escape mechanism in patients with inverted duplication and terminal deletion. Eur J Hum Genet 15(5):548–555
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408
Rossi E, Riegel M, Messa J, Gimelli S, Maraschio P, Ciccone R, Stroppi M, Riva P, Perrotta CS, Mattina T, Memo L, Baumer A, Kucinskas V, Castellan C, Schinzel A, Zuffardi O (2008) Duplications in addition to terminal deletions are present in a proportion of ring chromosomes: clues to the mechanisms of formation. J Med Genet 45(3):147–154
Schinzel A (2001) Catalogue of unbalanced chromosome aberrations in man. Walter de Gruyter, Berlin
Schlade-Bartusiak K, Costa T, Summers AM, Nowaczyk MJ, Cox DW (2005) FISH-mapping of telomeric 14q32 deletions: search for the cause of seizures. Am J Med Genet A 138A(3):218–224
Seghezzi L, Maraschio P, Bozzola M, Maserati E, Tupler R, Marchi A, Tiepolo L (1999) Ring chromosome 9 with a 9p22.3-p24.3 duplication. Eur J Pediatr 158(10):791–793
Sigurdardottir S, Goodman BK, Rutberg J, Thomas GH, Jabs EW, Geraghty MT (1999) Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of “complete ring” syndrome. Am J Med Genet 87(5):384–390
Surace C, Berardinelli F, Masotti A, Roberti MC, Da Sacco L, D’Elia G, Sirleto P, Digilio MC, Cusmai R, Grotta S, Petrocchi S, El Hachem M, Pisaneschi E, Ciocca L, Russo S, Lepri FR, Sgura A, Angioni A (2014) Telomere shortening and telomere position effect in mild ring 17 syndrome. Epigenetics Chromatin 7(1):1
van Karnebeek CD, Quik S, Sluijter S, Hulsbeek MM, Hoovers JM, Hennekam RC (2002) Further delineation of the chromosome 14q terminal deletion syndrome. Am J Med Genet 110(1):65–72
Ville D, De Bellescize J, Nguyen MA, Testard H, Gautier A, Perrier J, Till M, Des Portes V (2009) Ring 14 chromosome presenting as early-onset isolated partial epilepsy. Dev Med Child Neurol 51(11):917–922
Willcocks LC, Lyons PA, Clatworthy MR, Robinson JI, Yang W, Newland SA, Plagnol V, McGovern NN, Condliffe AM, Chilvers ER, Adu D, Jolly EC, Watts R, Lau YL, Morgan AW, Nash G, Smith KG (2008) Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 205(7):1573–1582
Zollino M, Seminara L, Orteschi D, Gobbi G, Giovannini S, Della Giustina E, Frattini D, Scarano A, Neri G (2009) The ring 14 syndrome: clinical and molecular definition. Am J Med Genet A 149A(6):1116–1124
Acknowledgements
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grant to RSG #2012/15572-7 and MIM #2012/51150-0).
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by: Michal Witt
Rights and permissions
About this article
Cite this article
Guilherme, R.S., Moysés-Oliveira, M., Dantas, A.G. et al. Position effect modifying gene expression in a patient with ring chromosome 14. J Appl Genetics 57, 183–187 (2016). https://doi.org/10.1007/s13353-015-0311-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13353-015-0311-8