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Hum Mol Genet
2008 Dec 01;1723:3655-62. doi: 10.1093/hmg/ddn260.
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Genetic and physical interaction between the NPHP5 and NPHP6 gene products.
Schäfer T
,
Pütz M
,
Lienkamp S
,
Ganner A
,
Bergbreiter A
,
Ramachandran H
,
Gieloff V
,
Gerner M
,
Mattonet C
,
Czarnecki PG
,
Sayer JA
,
Otto EA
,
Hildebrandt F
,
Kramer-Zucker A
,
Walz G
.
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Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease, caused by mutations of at least nine different genes. Several extrarenal manifestations characterize this disorder, including cerebellar defects, situs inversus and retinitis pigmentosa. While the clinical manifestations vary significantly in NPHP, mutations of NPHP5 and NPHP6 are always associated with progressive blindness. This clinical finding suggests that the gene products, nephrocystin-5 and nephrocystin-6, participate in overlapping signaling pathways to maintain photoreceptor homeostasis. To analyze the genetic interaction between these two proteins in more detail, we studied zebrafish embryos after depletion of NPHP5 and NPHP6. Knockdown of zebrafish zNPHP5 and zNPHP6 produced similar phenotypes, and synergistic effects were observed after the combined knockdown of zNPHP5 and zNPHP6. The N-terminal domain of nephrocystin-6-bound nephrocystin-5, and mapping studies delineated the interacting site from amino acid 696 to 896 of NPHP6. In Xenopus laevis, knockdown of NPHP5 caused substantial neural tube closure defects. This phenotype was copied by expression of the nephrocystin-5-binding fragment of nephrocystin-6, and rescued by co-expression of nephrocystin-5, supporting a physical interaction between both gene products in vivo. Since the N- and C-terminal fragments of nephrocystin-6 engage in the formation of homo- and heteromeric protein complexes, conformational changes seem to regulate the interaction of nephrocystin-6 with its binding partners.
Fig 7. Expression of nephrocystin-6 amino acids 665–1288 phenocopies the early developmental defects in Xenopus laevis caused by the depletion of neophrocystin-5. (A) X. laevis embryos were injected with either NPHP5 MO or RNA coding for amino acids 665–1288 of human nephrocystin-6 and/or full-length xNPHP5 into both dorsal blastomeres. At Nieuwkoop-Faber stage 19, embryos were analyzed for neural tube closure defects, and neural folds were visualized by sox3 in situ hybridization. (B) Depletion of NPHP5 resulted in neural tube closure defects in 80% of analyzed embryos (0.4 mm NPHP5 MO). (C) Expression of the nephrocystin-6 fragment amino acids 665–1288 caused prominent neural tube closure defects, while the expression of other truncations of nephrocystin-6 displayed only marginal effects (0.1 ng RNA). (D) Increasing doses of xNPHP5 RNA (0.25 and 0.5 ng) rescued the neural tube closure defects caused by the expression of nephrocystin-6 amino acids 665–1288 RNA (0.05 ng). In at least three independent experiments more than 90 embryos were injected in each group. Error bars represent standard deviation.
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