title: Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia.
abstract: Many genetic diseases have been linked to the dysfunction of primary cilia, which occur nearly ubiquitously in the body and act as solitary cellular mechanosensory organelles. The list of clinical manifestations and affected tissues in cilia-related disorders (ciliopathies) such as nephronophthisis is broad and has been attributed to the wide expression pattern of ciliary proteins. However, little is known about the molecular mechanisms leading to this dramatic diversity of phenotypes. We recently reported hypomorphic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration. Here, we chose a combinatorial approach in mice and humans to define the phenotypic spectrum of NPHP3/Nphp3 mutations and the role of the nephrocystin-3 protein. We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice. In humans, we show that NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects comprising situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT). On the functional level, we show that nephrocystin-3 directly interacts with inversin and can inhibit like inversin canonical Wnt signaling, whereas nephrocystin-3 deficiency leads in Xenopus laevis to typical planar cell polarity defects, suggesting a role in the control of canonical and noncanonical (planar cell polarity) Wnt signaling.
authors: Department of Human Genetics, RWTH Aachen University, 52074 Aachen, Germany. cbergmann@ukaachen.de
authors: Carsten
authors: C
authors: Bergmann
authors: Manfred
authors: M
authors: Fliegauf
authors: Nadina Ortiz
authors: NO
authors: Brüchle
authors: Valeska
authors: V
authors: Frank
authors: Heike
authors: H
authors: Olbrich
authors: Jan
authors: J
authors: Kirschner
authors: Bernhard
authors: B
authors: Schermer
authors: Ingolf
authors: I
authors: Schmedding
authors: Andreas
authors: A
authors: Kispert
authors: Bettina
authors: B
authors: Kränzlin
authors: Gudrun
authors: G
authors: Nürnberg
authors: Christian
authors: C
authors: Becker
authors: Tiemo
authors: T
authors: Grimm
authors: Gundula
authors: G
authors: Girschick
authors: Sally A
authors: SA
authors: Lynch
authors: Peter
authors: P
authors: Kelehan
authors: Jan
authors: J
authors: Senderek
authors: Thomas J
authors: TJ
authors: Neuhaus
authors: Thomas
authors: T
authors: Stallmach
authors: Hanswalter
authors: H
authors: Zentgraf
authors: Peter
authors: P
authors: Nürnberg
authors: Norbert
authors: N
authors: Gretz
authors: Cecilia
authors: C
authors: Lo
authors: Soeren
authors: S
authors: Lienkamp
authors: Tobias
authors: T
authors: Schäfer
authors: Gerd
authors: G
authors: Walz
authors: Thomas
authors: T
authors: Benzing
authors: Klaus
authors: K
authors: Zerres
authors: Heymut
authors: H
authors: Omran
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002648:Child; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000002:abnormalities; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000002:abnormalities; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010179:Pancreas / Q000002:abnormalities; D010375:Pedigree; D012857:Situs Inversus / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C114503:INVS protein, human; D014157:Transcription Factors; D051153:Wnt Proteins; C528697:nephrocystin-3, human; C528698:nephrocystin-3, mouse; D016547:Kinesins