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Am J Hum Genet 2008 Apr 01;824:959-70. doi: 10.1016/j.ajhg.2008.02.017.
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Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia.

Bergmann C , Fliegauf M , Brüchle NO , Frank V , Olbrich H , Kirschner J , Schermer B , Schmedding I , Kispert A , Kränzlin B , Nürnberg G , Becker C , Grimm T , Girschick G , Lynch SA , Kelehan P , Senderek J , Neuhaus TJ , Stallmach T , Zentgraf H , Nürnberg P , Gretz N , Lo C , Lienkamp S , Schäfer T , Walz G , Benzing T , Zerres K , Omran H .

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.

PubMed ID: 18371931
PMC ID: PMC2427297
Article link: Am J Hum Genet

Species referenced: Xenopus laevis
Genes referenced: ahi1 ccdc28b cep290 invs lef1 nphp1 nphp3 ofd1 rpgrip1l tcf3
Morpholinos: nphp3 MO1

Disease Ontology terms: Senior-Loken syndrome [+]
References [+] :
Arts, Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. 2007, Pubmed