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Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature

Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature
Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasias, often in combination with asplenia. In a further four generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which co-segregated with the disease in this large family with a LOD score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen. This article is protected by copyright. All rights reserved.

1059-7794
196-202
Kerkhofs, Chantal
207d2f58-0600-4a3c-b0f5-55b645b218c8
Stevens, Servi J C
26582896-2b0e-4524-a5d9-1894e2027338
Faust, Saul N
f97df780-9f9b-418e-b349-7adf63e150c1
Rae, William
8746e0ae-b868-4356-9c89-fe78600cf427
Williams, Anthony P
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Wurm, Peter
c9134f72-4bab-4cc8-aaf6-f2a6925a653d
Østern, Rune
014b2d57-0b48-4c63-8ef4-325ec558d0ac
Fockens, Paul
83c936ea-f69d-4e00-8562-e27c551a6622
Würfel, Christiane
6963d989-6efb-47b4-b5ca-a47965a2462d
Laass, Martin
c9224183-ecb3-497e-b18f-3942c448440b
Kokke, Freddy
fe8191ff-3f29-4422-8696-7c3e25b2c57c
Stegmann, Alexander P A
6a766f02-b76d-4ae1-8c80-1a24cfd174db
Brunner, Han G
05804df4-c21b-4b65-b87c-e1cefe53713e
Kerkhofs, Chantal
207d2f58-0600-4a3c-b0f5-55b645b218c8
Stevens, Servi J C
26582896-2b0e-4524-a5d9-1894e2027338
Faust, Saul N
f97df780-9f9b-418e-b349-7adf63e150c1
Rae, William
8746e0ae-b868-4356-9c89-fe78600cf427
Williams, Anthony P
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Wurm, Peter
c9134f72-4bab-4cc8-aaf6-f2a6925a653d
Østern, Rune
014b2d57-0b48-4c63-8ef4-325ec558d0ac
Fockens, Paul
83c936ea-f69d-4e00-8562-e27c551a6622
Würfel, Christiane
6963d989-6efb-47b4-b5ca-a47965a2462d
Laass, Martin
c9224183-ecb3-497e-b18f-3942c448440b
Kokke, Freddy
fe8191ff-3f29-4422-8696-7c3e25b2c57c
Stegmann, Alexander P A
6a766f02-b76d-4ae1-8c80-1a24cfd174db
Brunner, Han G
05804df4-c21b-4b65-b87c-e1cefe53713e

Kerkhofs, Chantal, Stevens, Servi J C, Faust, Saul N, Rae, William, Williams, Anthony P, Wurm, Peter, Østern, Rune, Fockens, Paul, Würfel, Christiane, Laass, Martin, Kokke, Freddy, Stegmann, Alexander P A and Brunner, Han G (2019) Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature. Human Mutation, 41 (1), 196-202. (doi:10.1002/humu.23909).

Record type: Article

Abstract

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasias, often in combination with asplenia. In a further four generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which co-segregated with the disease in this large family with a LOD score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen. This article is protected by copyright. All rights reserved.

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Kerkhofs_et_al-2019-Human_Mutation - Accepted Manuscript
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Accepted/In Press date: 2 September 2019
e-pub ahead of print date: 9 September 2019

Identifiers

Local EPrints ID: 434118
URI: http://eprints.soton.ac.uk/id/eprint/434118
ISSN: 1059-7794
PURE UUID: 86f75067-6281-4384-91c6-4477a4df711a
ORCID for Saul N Faust: ORCID iD orcid.org/0000-0003-3410-7642

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Date deposited: 13 Sep 2019 16:30
Last modified: 26 Nov 2021 02:50

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Contributors

Author: Chantal Kerkhofs
Author: Servi J C Stevens
Author: Saul N Faust ORCID iD
Author: William Rae
Author: Peter Wurm
Author: Rune Østern
Author: Paul Fockens
Author: Christiane Würfel
Author: Martin Laass
Author: Freddy Kokke
Author: Alexander P A Stegmann
Author: Han G Brunner

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