Separation of the PROX1 gene from upstream conserved elements in a complex inversion/translocation patient with hypoplastic left heart
Separation of the PROX1 gene from upstream conserved elements in a complex inversion/translocation patient with hypoplastic left heart
Hypoplastic left heart (HLH) occurs in at least 1 in 10 000 live births but may be more common in utero. Its causes are poorly understood but a number of affected cases are associated with chromosomal abnormalities. We set out to localize the breakpoints in a patient with sporadic HLH and a de novo translocation. Initial studies showed that the apparently simple 1q41;3q27.1 translocation was actually combined with a 4-Mb inversion, also de novo, of material within 1q41. We therefore localized all four breakpoints and found that no known transcription units were disrupted. However we present a case, based on functional considerations, synteny and position of highly conserved non-coding sequence elements, and the heterozygous Prox1(+/-) mouse phenotype (ventricular hypoplasia), for the involvement of dysregulation of the PROX1 gene in the aetiology of HLH in this case. Accordingly, we show that the spatial expression pattern of PROX1 in the developing human heart is consistent with a role in cardiac development. We suggest that dysregulation of PROX1 gene expression due to separation from its conserved upstream elements is likely to have caused the heart defects observed in this patient, and that PROX1 should be considered as a potential candidate gene for other cases of HLH. The relevance of another breakpoint separating the cardiac gene ESRRG from a conserved downstream element is also discussed
chromosome inversion, chromosome translocation, PROX1, hypoplastic left heart, position effect
1423-1431
Gill, Harinder K.
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Parsons, Sian R.
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Spalluto, Cosma
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Davies, AngelaF.
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Knorz, Victoria J.
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Burlinson, Clare E.G.
13420c6b-2ce5-47a3-aa08-433c353731cc
Ng, Bee Ling
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Carter, Nigel P.
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Ogilvie, Caroline Makie
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Wilson, David I.
1500fca1-7082-4271-95f4-691f1d1252a2
Roberts, Roland G.
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November 2009
Gill, Harinder K.
35f6a22f-5565-44a2-a634-3baeaeeac798
Parsons, Sian R.
3a311252-377e-403a-b857-5213102cbbe4
Spalluto, Cosma
6802ad50-bc38-404f-9a19-40916425183b
Davies, AngelaF.
320bf71e-3a12-4b77-be23-eff6edde0cab
Knorz, Victoria J.
f0084ead-54c9-4885-b60e-9360dcf3d524
Burlinson, Clare E.G.
13420c6b-2ce5-47a3-aa08-433c353731cc
Ng, Bee Ling
d569ce7f-b642-4166-81ee-cc718d50a0b0
Carter, Nigel P.
f79b7469-f7fb-40b5-827d-2baf7199c508
Ogilvie, Caroline Makie
2c3ca357-c655-4762-a5e2-5e1bfe3f9422
Wilson, David I.
1500fca1-7082-4271-95f4-691f1d1252a2
Roberts, Roland G.
c60fb62b-6e98-4608-aa02-4aac0b2a9806
Gill, Harinder K., Parsons, Sian R., Spalluto, Cosma, Davies, AngelaF., Knorz, Victoria J., Burlinson, Clare E.G., Ng, Bee Ling, Carter, Nigel P., Ogilvie, Caroline Makie, Wilson, David I. and Roberts, Roland G.
(2009)
Separation of the PROX1 gene from upstream conserved elements in a complex inversion/translocation patient with hypoplastic left heart.
European Journal of Human Genetics, 17 (11), .
(doi:10.1038/ejhg.2009.91).
Abstract
Hypoplastic left heart (HLH) occurs in at least 1 in 10 000 live births but may be more common in utero. Its causes are poorly understood but a number of affected cases are associated with chromosomal abnormalities. We set out to localize the breakpoints in a patient with sporadic HLH and a de novo translocation. Initial studies showed that the apparently simple 1q41;3q27.1 translocation was actually combined with a 4-Mb inversion, also de novo, of material within 1q41. We therefore localized all four breakpoints and found that no known transcription units were disrupted. However we present a case, based on functional considerations, synteny and position of highly conserved non-coding sequence elements, and the heterozygous Prox1(+/-) mouse phenotype (ventricular hypoplasia), for the involvement of dysregulation of the PROX1 gene in the aetiology of HLH in this case. Accordingly, we show that the spatial expression pattern of PROX1 in the developing human heart is consistent with a role in cardiac development. We suggest that dysregulation of PROX1 gene expression due to separation from its conserved upstream elements is likely to have caused the heart defects observed in this patient, and that PROX1 should be considered as a potential candidate gene for other cases of HLH. The relevance of another breakpoint separating the cardiac gene ESRRG from a conserved downstream element is also discussed
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Published date: November 2009
Keywords:
chromosome inversion, chromosome translocation, PROX1, hypoplastic left heart, position effect
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Local EPrints ID: 69626
URI: http://eprints.soton.ac.uk/id/eprint/69626
ISSN: 1018-4813
PURE UUID: 7edc254b-4522-4b7c-8975-19a409486b33
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Date deposited: 20 Nov 2009
Last modified: 14 Mar 2024 02:46
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Contributors
Author:
Harinder K. Gill
Author:
Sian R. Parsons
Author:
Cosma Spalluto
Author:
AngelaF. Davies
Author:
Victoria J. Knorz
Author:
Clare E.G. Burlinson
Author:
Bee Ling Ng
Author:
Nigel P. Carter
Author:
Caroline Makie Ogilvie
Author:
Roland G. Roberts
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