Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia.
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.
Bergmann
Carsten
C
Department of Human Genetics, RWTH Aachen University, 52074 Aachen, Germany. cbergmann@ukaachen.de
Fliegauf
Manfred
M
Brüchle
Nadina Ortiz
NO
Frank
Valeska
V
Olbrich
Heike
H
Kirschner
Jan
J
Schermer
Bernhard
B
Schmedding
Ingolf
I
Kispert
Andreas
A
Kränzlin
Bettina
B
Nürnberg
Gudrun
G
Becker
Christian
C
Grimm
Tiemo
T
Girschick
Gundula
G
Lynch
Sally A
SA
Kelehan
Peter
P
Senderek
Jan
J
Neuhaus
Thomas J
TJ
Stallmach
Thomas
T
Zentgraf
Hanswalter
H
Nürnberg
Peter
P
Gretz
Norbert
N
Lo
Cecilia
C
Lienkamp
Soeren
S
Schäfer
Tobias
T
Walz
Gerd
G
Benzing
Thomas
T
Zerres
Klaus
K
Omran
Heymut
H
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
C114503:INVS protein, human; D014157:Transcription Factors; D051153:Wnt Proteins; C528697:nephrocystin-3, human; C528698:nephrocystin-3, mouse; D016547:Kinesins