Early presentation of cystic kidneys in a family with a homozygous INVS mutation
Publication year
2014Source
American Journal of Medical Genetics. Part A, 164, 7, (2014), pp. 1627-34ISSN
Publication type
Article / Letter to editor
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Organization
Human Genetics
Pathology
Journal title
American Journal of Medical Genetics. Part A
Volume
vol. 164
Issue
iss. 7
Page start
p. 1627
Page end
p. 34
Subject
Radboudumc 0: Other Research RIHS: Radboud Institute for Health Sciences; Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Radboudumc 7: Neurodevelopmental disorders RIMLS: Radboud Institute for Molecular Life SciencesAbstract
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is the most frequent monogenic cause of end-stage renal disease in children. Infantile NPHP, often in combination with other features like situs inversus, are commonly caused by mutations in the INVS gene. INVS encodes the ciliary protein inversin, and mutations induce dysfunction of the primary cilia. In this article, we present a family with two severely affected fetuses that were aborted after discovery of grossly enlarged cystic kidneys by ultrasonography before 22 weeks gestation. Exome sequencing showed that the fetuses were homozygous for a previously unreported nonsense mutation, resulting in a truncation in the IQ1 domain of inversin. This mutation induces nonsense-mediated RNA decay, as suggested by a reduced RNA level in fibroblasts derived from the fetus. However, a significant amount of mutant INVS RNA was present in these fibroblasts, yielding mutant inversin protein that was mislocalized. In control fibroblasts, inversin was present in the ciliary axoneme as well as at the basal body, whereas in the fibroblasts from the fetus, inversin could only be detected at the basal body. The phenotype of both fetuses is partly characteristic of infantile NPHP and Potter sequence. We also identified that the fetuses had mild skeletal abnormalities, including shortening and bowing of long bones, which may expand the phenotypic spectrum associated with INVS mutations. (c) 2014 Wiley Periodicals, Inc.
This item appears in the following Collection(s)
- Academic publications [238586]
- Electronic publications [122829]
- Faculty of Medical Sciences [90409]
- Open Access publications [97813]
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