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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
.
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.
Arts,
Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
2007, Pubmed
Arts,
Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
2007,
Pubmed
Baala,
The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.
2007,
Pubmed
Baala,
Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome.
2007,
Pubmed
Badano,
Dissection of epistasis in oligogenic Bardet-Biedl syndrome.
2006,
Pubmed
Badano,
The ciliopathies: an emerging class of human genetic disorders.
2006,
Pubmed
Benzing,
Nephrocystin interacts with Pyk2, p130(Cas), and tensin and triggers phosphorylation of Pyk2.
2001,
Pubmed
Chiang,
Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11).
2006,
Pubmed
Christensen,
Sensory cilia and integration of signal transduction in human health and disease.
2007,
Pubmed
Delous,
The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.
2007,
Pubmed
Ferrante,
Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.
2006,
Pubmed
Fliegauf,
Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia.
2006,
Pubmed
Frank,
Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome.
2008,
Pubmed
Frank,
Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber syndrome.
2007,
Pubmed
Gerdes,
Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response.
2007,
Pubmed
Harris,
Understanding pathogenic mechanisms in polycystic kidney disease provides clues for therapy.
2006,
Pubmed
Hildebrandt,
Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease?
2005,
Pubmed
Hoefele,
Evidence of oligogenic inheritance in nephronophthisis.
2007,
Pubmed
Jaeken,
Congenital disorders of glycosylation: a booming chapter of pediatrics.
2004,
Pubmed
Kim,
The polycystic kidney disease 1 gene product modulates Wnt signaling.
1999,
Pubmed
Levanon,
The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons.
2002,
Pubmed
Mollet,
Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes.
2005,
Pubmed
Moyer,
Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice.
1994,
Pubmed
Murcia,
The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination.
2000,
Pubmed
,
Xenbase
Mykytyn,
Clinical variability in ciliary disorders.
2007,
Pubmed
Neuhaus,
Renal-hepatic-pancreatic dysplasia: an autosomal recessive disorder with renal and hepatic failure.
1996,
Pubmed
Newport,
A major developmental transition in early Xenopus embryos: I. characterization and timing of cellular changes at the midblastula stage.
1982,
Pubmed
,
Xenbase
Newport,
Regulation of the cell cycle during early Xenopus development.
1984,
Pubmed
,
Xenbase
Olbrich,
Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis.
2003,
Pubmed
Omran,
Human adolescent nephronophthisis: gene locus synteny with polycystic kidney disease in pcy mice.
2001,
Pubmed
Otto,
Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.
2003,
Pubmed
Rankin,
The laminopathies: a clinical review.
2006,
Pubmed
Ross,
Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates.
2005,
Pubmed
Simons,
Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways.
2005,
Pubmed
,
Xenbase
Torres,
Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases.
2006,
Pubmed
Tory,
High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations.
2007,
Pubmed
Vierkotten,
Ftm is a novel basal body protein of cilia involved in Shh signalling.
2007,
Pubmed
Woo,
Genetic identification of two major modifier loci of polycystic kidney disease progression in pcy mice.
1997,
Pubmed
