Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature.
Blood Vessels
/ abnormalities
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Homeodomain Proteins
/ genetics
Humans
Intestines
/ blood supply
Male
Mutation
Organogenesis
/ genetics
Pedigree
Receptors, Laminin
/ genetics
Ribosomal Proteins
/ genetics
Sequence Analysis, DNA
Spleen
/ blood supply
Transcription Factors
/ genetics
Exome Sequencing
NKX2-3
RPSA
asplenia
homeobox gene
intestinal varices
whole-exome sequencing
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
22
05
2019
revised:
28
08
2019
accepted:
02
09
2019
pubmed:
10
9
2019
medline:
20
5
2021
entrez:
10
9
2019
Statut:
ppublish
Résumé
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 angiodysplasia, 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 cosegregated with the disease in this large family with a LOD (logarithm of the odds) 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.
Identifiants
pubmed: 31498527
doi: 10.1002/humu.23909
pmc: PMC6972609
doi:
Substances chimiques
Homeodomain Proteins
0
NKX2-3 protein, human
0
RPSA protein, human
0
Receptors, Laminin
0
Ribosomal Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
196-202Informations de copyright
© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.
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