ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3
Soeren Lienkamp, Carsten Bergmann, Friedhelm Hildebrandt and colleagues show that mutations in ANKS6 cause nephronophthisis, a recessive cystic kidney disease. They further identify ANKS6 as a component of a protein module that includes INVS (NPHP2), NPHP3 and NEK8 (NPHP9). Nephronophthisis is an au...
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Veröffentlicht in: | Nature genetics 2013-08, Vol.45 (8), p.951-956 |
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Zusammenfassung: | Soeren Lienkamp, Carsten Bergmann, Friedhelm Hildebrandt and colleagues show that mutations in
ANKS6
cause nephronophthisis, a recessive cystic kidney disease. They further identify ANKS6 as a component of a protein module that includes INVS (NPHP2), NPHP3 and NEK8 (NPHP9).
Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and
Xenopus laevis
. We also identify six families with
ANKS6
mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and
situs inversus
. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of
Hif1an
in
Xenopus
results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in
ANKS6
,
NEK8
,
INVS
or
NPHP3
. |
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ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/ng.2681 |