doi: 10.1007/s10577-009-9059-5. Epub 2009 Aug 12.
Implication of long-distance regulation of the HOXA cluster in a patient with postaxial polydactyly
Affiliations
- PMID:19672683
- PMCID: PMC2759026
- DOI: 10.1007/s10577-009-9059-5
Item in Clipboard
Implication of long-distance regulation of the HOXA cluster in a patient with postaxial polydactyly
Elisabeth M Lodder et al. Chromosome Res.2009.
Display options
Format
Display options
Format
Abstract
Apparently balanced chromosomal inversions may lead to disruption of developmentally important genes at the breakpoints of the inversion, causing congenital malformations. Characterization of such inversions may therefore lead to new insights in human development. Here, we report on a de novo inversion of chromosome 7 (p15.2q36.3) in a patient with postaxial polysyndactyly. The breakpoints do not disrupt likely candidate genes for the limb phenotype observed in the patient. However, on the p-arm the breakpoint separates the HOXA cluster from a gene desert containing several conserved noncoding elements, suggesting that a disruption of a cis-regulatory circuit of the HOXA cluster could be the underlying cause of the phenotype in this patient.
Figures
Detailed mapping of the inversion breakpoints (a) CTG banding of chromosome 7 breakpoints of the inversion are indicated by stars. (b) Affymetrix SNP array results for chromosome 7, revealing no large deletions or duplications; breakpoints of the inversion are indicated by stars, (c) FISH analysis of the breakpoint on 7q showing G248P85855B2 (green signal swaps to 7p) and G248P89016G3 (red, split signal). (d) Southern blot analysis of probe P15, P20, and Q40 showing abnormal sized bands in the patient (p) and not in the control (c). (e) FISH analysis of the breakpoint on 7p showing separation of fosmids G248P81811A6 (red stays on p) and G248P89547A12 (green, swaps to q). (f, g) Sequence analysis of the breakpoints 7p (f, rev) and 7q (g, rev). Green, blue, and red lines indicate sequence from 7p, 7q, and duplicated sequence from 7p respectively
Overview of the inversion on chromosome 7: From top to bottom: karyogram of chromosome 7 (based on the Ensembl genome browserhttp://www.ensembl.org/ ). Black rectangle: area of the breakpoint on 7p; gray rectangle: area of the breakpoint on 7q. Locations of the BACs (RP11-66O14 and RP11-51L24) and fosmids A6 (G248P81811A6), A12 (G248P89547A12), B2(G248P85855B2), and G3 (G248P89016G3), and probe Q40 are indicated by lines. Genomic context (not to scale) of the breakpoints (BP), indicating the position of genes flanking the breakpoints and those of particular interest due to their role in limb development (ZRS: limb specific SHH cis-regulatory element). Homology plot of NFE2L3 (http://www.gSD.lbl.gov/vista ); stretches of homology >75% between human and mouse are indicated in gray. The line marks the position of the breakpoint, the rectangles indicate the deletions, e1–4 mark the positions of the exons, and probes P15 and P20 are indicated by lines
Similar articles
- Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.Lohan S, Spielmann M, Doelken SC, Flöttmann R, Muhammad F, Baig SM, Wajid M, Hülsemann W, Habenicht R, Kjaer KW, Patil SJ, Girisha KM, Abarca-Barriga HH, Mundlos S, Klopocki E.Lohan S, et al.Clin Genet. 2014 Oct;86(4):318-25. doi: 10.1111/cge.12352. Epub 2014 Feb 17.Clin Genet. 2014.PMID:24456159
- A Chromosome 7 Pericentric Inversion Defined at Single-Nucleotide Resolution Using Diagnostic Whole Genome Sequencing in a Patient with Hand-Foot-Genital Syndrome.Watson CM, Crinnion LA, Harrison SM, Lascelles C, Antanaviciute A, Carr IM, Bonthron DT, Sheridan E.Watson CM, et al.PLoS One. 2016 Jun 7;11(6):e0157075. doi: 10.1371/journal.pone.0157075. eCollection 2016.PLoS One. 2016.PMID:27272187Free PMC article.
- Characterization of two ectrodactyly-associated translocation breakpoints separated by 2.5 Mb on chromosome 2q14.1-q14.2.David D, Marques B, Ferreira C, Vieira P, Corona-Rivera A, Ferreira JC, van Bokhoven H.David D, et al.Eur J Hum Genet. 2009 Aug;17(8):1024-33. doi: 10.1038/ejhg.2009.2. Epub 2009 Feb 18.Eur J Hum Genet. 2009.PMID:19223936Free PMC article.
- Human HOX gene mutations.Goodman FR, Scambler PJ.Goodman FR, et al.Clin Genet. 2001 Jan;59(1):1-11. doi: 10.1034/j.1399-0004.2001.590101.x.Clin Genet. 2001.PMID:11206481Review.
- Limb malformations and the human HOX genes.Goodman FR.Goodman FR.Am J Med Genet. 2002 Oct 15;112(3):256-65. doi: 10.1002/ajmg.10776.Am J Med Genet. 2002.PMID:12357469Review.
Cited by
- cis-regulatory mutations are a genetic cause of human limb malformations.VanderMeer JE, Ahituv N.VanderMeer JE, et al.Dev Dyn. 2011 May;240(5):920-30. doi: 10.1002/dvdy.22535. Epub 2011 Jan 11.Dev Dyn. 2011.PMID:21509892Free PMC article.Review.
- Disruption of long-range gene regulation in human genetic disease: a kaleidoscope of general principles, diverse mechanisms and unique phenotypic consequences.Bhatia S, Kleinjan DA.Bhatia S, et al.Hum Genet. 2014 Jul;133(7):815-45. doi: 10.1007/s00439-014-1424-6. Epub 2014 Feb 5.Hum Genet. 2014.PMID:24496500Review.
- Efficient discovery of ASCL1 regulatory sequences through transgene pooling.McGaughey DM, McCallion AS.McGaughey DM, et al.Genomics. 2010 Jun;95(6):363-9. doi: 10.1016/j.ygeno.2010.02.011. Epub 2010 Mar 4.Genomics. 2010.PMID:20206680Free PMC article.
- Current concepts of follicle-stimulating hormone receptor gene regulation.George JW, Dille EA, Heckert LL.George JW, et al.Biol Reprod. 2011 Jan;84(1):7-17. doi: 10.1095/biolreprod.110.085043. Epub 2010 Aug 25.Biol Reprod. 2011.PMID:20739665Free PMC article.Review.
References
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.ydbio.2005.11.013', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.ydbio.2005.11.013'}, {'type': 'PubMed', 'value': '16458883', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/16458883/'}]}
- Bagheri-Fam S, Barrionuevo F, Dohrmann U et al (2006) Long-range upstream and downstream enhancers control distinct subsets of the complex spatiotemporal Sox9 expression pattern. Dev Biol 291:382–397 - PubMed
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/hmg/ddm061', 'is_inner': False, 'url': 'https://doi.org/10.1093/hmg/ddm061'}, {'type': 'PubMed', 'value': '17409199', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/17409199/'}]}
- Bien-Willner GA, Stankiewicz P, Lupski JR (2007) SOX9cre1: a cis-acting regulatory element located 1.1 Mb upstream of SOX9: mediates its enhancement through the SHH pathway. Hum Mol Genet 16:1143–1156 - PubMed
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15709245', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/15709245/'}]}
- Bliek JB, de Klein A, Luider TM et al (2004) New approach for the identification of folate-related pathways in human embryogenesis. Cell Mol Biol (Noisy-le-grand 50:939–944 - PubMed
- {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/(SICI)1096-8628(19981228)80:5<459::AID-AJMG5>3.0.CO;2-G', 'is_inner': False, 'url': 'https://doi.org/10.1002/(sici)1096-8628(19981228)80:5<459::aid-ajmg5>3.0.co;2-g'}, {'type': 'PubMed', 'value': '9880209', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9880209/'}]}
- Castilla EE, Lugarinho R, da Graca Dutra M, Salgado LJ (1998) Associated anomalies in individuals with polydactyly. Am J Med Genet 80:459–465 - PubMed
Publication types
MeSH terms
Substances
Related information
LinkOut - more resources
Full Text Sources