title: Early presentation of cystic kidneys in a family with a homozygous INVS mutation.
abstract: 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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Oud
authors.forename: Bregje W
authors.initials: BW
authors.lastname: van Bon
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Marcelis
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.forename: Suzanne J J
authors.initials: SJ
authors.lastname: Mol
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
mesh_terms: D037881:Aborted Fetus / Q000473:pathology; D055028:Comparative Genomic Hybridization; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D052177:Kidney Diseases, Cystic / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D016216:Ultrasonography, Prenatal
chemical_list: C114503:INVS protein, human; D014157:Transcription Factors
keywords: INVS; Infantile NPHP; Potter sequence