Loss of Nephrocystin-3 Function Can Cause Embryonic Lethality, Meckel-Gruber-like Syndrome, Situs Inversus, and Renal-Hepatic-Pancreatic Dysplasia

• Published in: American journal of human genetics Vol. 82; no. 4; pp. 959 - 970
• Main Authors: Bergmann, Carsten, Fliegauf, Manfred, Brüchle, Nadina Ortiz, Frank, Valeska, Olbrich, Heike, Kirschner, Jan, Schermer, Bernhard, Schmedding, Ingolf, Kispert, Andreas, Kränzlin, Bettina, Nürnberg, Gudrun, Becker, Christian, Grimm, Tiemo, Girschick, Gundula, Lynch, Sally A., Kelehan, Peter, Senderek, Jan, Neuhaus, Thomas J., Stallmach, Thomas, Zentgraf, Hanswalter, Nürnberg, Peter, Gretz, Norbert, Lo, Cecilia, Lienkamp, Soeren, Schäfer, Tobias, Walz, Gerd, Benzing, Thomas, Zerres, Klaus, Omran, Heymut
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.04.2008; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Animals; Biological and medical sciences; Cells; Child; Female; Fetal Death - genetics; Fundamental and applied biological sciences. Psychology; Gene expression; General aspects. Genetic counseling; Genes; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Humans; Infant, Newborn; Kidney - abnormalities; Kidney diseases; Kidney Diseases, Cystic - genetics; Kinesins - genetics; Kinesins - metabolism; Liver - abnormalities; Male; Malformations of the nervous system; Medical genetics; Medical sciences; Mice; Mice, Mutant Strains; Molecular and cellular biology; Mutation; Neurology; Pancreas - abnormalities; Pedigree; Signal transduction; Situs Inversus - genetics; Syndrome; Transcription Factors - metabolism; Wnt Proteins - metabolism; Xenopus laevis; Kidney disease; Human; Nervous system diseases; Urinary system disease; Liver; Diseases of the osteoarticular system; Situs inversus; Renal dysplasia; Congenital disease; Genetic disease; Loss function; Malformation; Digestive diseases; Genetics; Pancreas; Meckel syndrome
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2008.02.017

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.