General Information:

Id: 7,121
Diseases: Nephronophthisis
Mammalia
review
Reference: Hildebrandt F et al.(2009) Nephronophthisis: disease mechanisms of a ciliopathy J. Am. Soc. Nephrol. 20: 23-35 [PMID: 19118152]

Interaction Information:

Comment Nephrocystin-1 and inversin/NPHP2 localize to primary cilia of renal tubular cells.
Formal Description
Interaction-ID: 70096

gene/protein

NPHP1

is localized in

cellular component

cilium

in renal tubular cells
Comment Nephrocystin-1 and inversin/NPHP2 localize to primary cilia of renal tubular cells.
Formal Description
Interaction-ID: 70097

gene/protein

INVS

is localized in

cellular component

cilium

in renal tubular cells
Comment Mutations in NPHP1 were identified as causing juvenile nephronophthisis type 1. NPHP1 encodes nephrocystin-1, a protein that interacts with components of cell-cell and cell-matrix signaling, including p130Cas, focal adhesion kinase 2, tensin, and filamin A and B.
Formal Description
Interaction-ID: 70098

gene/protein mutant

NPHP1-mut

increases_activity of

Comment Mutations in NPHP1 were identified as causing juvenile nephronophthisis type 1. NPHP1 encodes nephrocystin-1, a protein that interacts with components of cell-cell and cell-matrix signaling, including p130Cas, focal adhesion kinase 2, tensin, and filamin A and B.
Formal Description
Interaction-ID: 70101

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

BCAR1

Comment Mutations in NPHP1 were identified as causing juvenile nephronophthisis type 1. NPHP1 encodes nephrocystin-1, a protein that interacts with components of cell-cell and cell-matrix signaling, including p130Cas, focal adhesion kinase 2, tensin, and filamin A and B.
Formal Description
Interaction-ID: 70102

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

PTK2B

Drugbank entries Show/Hide entries for PTK2B
Comment Mutations in NPHP1 were identified as causing juvenile nephronophthisis type 1. NPHP1 encodes nephrocystin-1, a protein that interacts with components of cell-cell and cell-matrix signaling, including p130Cas, focal adhesion kinase 2, tensin, and filamin A and B.
Formal Description
Interaction-ID: 70103

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

TNS

Comment Mutations in NPHP1 were identified as causing juvenile nephronophthisis type 1. NPHP1 encodes nephrocystin-1, a protein that interacts with components of cell-cell and cell-matrix signaling, including p130Cas, focal adhesion kinase 2, tensin, and filamin A and B.
Formal Description
Interaction-ID: 70104

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

FLNA

Comment Mutations in NPHP1 were identified as causing juvenile nephronophthisis type 1. NPHP1 encodes nephrocystin-1, a protein that interacts with components of cell-cell and cell-matrix signaling, including p130Cas, focal adhesion kinase 2, tensin, and filamin A and B.
Formal Description
Interaction-ID: 70105

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

FLNB

Comment Nephrocystin-1 is located at adherens junctions and focal adhesions of renal epithelial cells, which are involved in cell-cell and cell-basement membrane contacts, respectively.
Formal Description
Interaction-ID: 70106

gene/protein

NPHP1

is localized in

cellular component

adherens junction

in renal epithelial cells
Comment Nephrocystin-1 is located at adherens junctions and focal adhesions of renal epithelial cells, which are involved in cell-cell and cell-basement membrane contacts, respectively.
Formal Description
Interaction-ID: 70107

gene/protein

NPHP1

is localized in

cellular component

focal adhesion

in renal epithelial cells
Comment Nephrocystin-1 interacts with the products of other nephronophthisis genes such as nephrocystin-2/inversin, nephrocystin-3, and nephrocystin-4.
Formal Description
Interaction-ID: 70108

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

INVS

Comment Nephrocystin-1 interacts with the products of other nephronophthisis genes such as nephrocystin-2/inversin, nephrocystin-3, and nephrocystin-4.
Formal Description
Interaction-ID: 70109

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

NPHP3

Comment Nephrocystin-1 interacts with the products of other nephronophthisis genes such as nephrocystin-2/inversin, nephrocystin-3, and nephrocystin-4.
Formal Description
Interaction-ID: 70110

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

NPHP4

Comment Nephrocystin-1 is targeted to the transition zone of motile and primary cilia by the protein phosphofurin acidic cluster sorting protein 1 (PACS-1). This is initiated by casein kinase 2–mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin, leading to PACS-1 binding and co-localization of nephrocystin with PACS-1 at the base of cilia.
Formal Description
Interaction-ID: 70111

gene/protein

PACS1

increases_transport of

gene/protein

NPHP1

to the transition zone of motile and primary cilia
Comment Mutations in human inversin (INVS) were identified as the cause of infantile NPHP (type 2) with and without situs inversus. The renal cystic changes of infantile nephronophthisis (NPHP type 2) combine clinical features of NPHP and of polycystic kidney disease (PKD).
Formal Description
Interaction-ID: 70112

gene/protein mutant

INVS-mut

increases_activity of

Comment Nephrocystin-1 and NPHP2/inversin interact with beta-tubulin, which constitutes the microtubule axoneme of primary cilia, and they localize at primary cilia of renal tubular cells.
Formal Description
Interaction-ID: 70113

gene/protein

NPHP1

interacts (colocalizes) with

gene/protein

TUBB

Drugbank entries Show/Hide entries for TUBB
Comment Nephrocystin-1 and NPHP2/inversin interact with beta-tubulin, which constitutes the microtubule axoneme of primary cilia, and they localize at primary cilia of renal tubular cells.
Formal Description
Interaction-ID: 70114

gene/protein

INVS

interacts (colocalizes) with

gene/protein

TUBB

Drugbank entries Show/Hide entries for TUBB
Comment Nephrocystin-1 and NPHP2/inversin interact with beta-tubulin, which constitutes the microtubule axoneme of primary cilia, and they localize at primary cilia of renal tubular cells.
Formal Description
Interaction-ID: 70115

gene/protein

TUBB

is localized in

cellular component

axoneme

Drugbank entries Show/Hide entries for TUBB
Comment Inversin was shown to localize to different subcellular locations, in a cell cycle-dependent manner. It is found at the mitotic spindle in mitosis, at the mid-body in cytokinesis, and in cilia at the basal body and centrosome in interphase. All of these subcellular organelles are involved in regulation of planar cell polarity or the cell cycle.
Formal Description
Interaction-ID: 70116

gene/protein

INVS

is localized in

cellular component

mitotic spindle

in mitosis
Comment Inversin was shown to localize to different subcellular locations, in a cell cycle-dependent manner. It is found at the mitotic spindle in mitosis, at the mid-body in cytokinesis, and in cilia at the basal body and centrosome in interphase. All of these subcellular organelles are involved in regulation of planar cell polarity or the cell cycle.
Formal Description
Interaction-ID: 70117

gene/protein

INVS

is localized in

cellular component

midbody

in cytokinesis
Comment Inversin was shown to localize to different subcellular locations, in a cell cycle-dependent manner. It is found at the mitotic spindle in mitosis, at the mid-body in cytokinesis, and in cilia at the basal body and centrosome in interphase. All of these subcellular organelles are involved in regulation of planar cell polarity or the cell cycle.
Formal Description
Interaction-ID: 70118

gene/protein

INVS

is localized in

cellular component

ciliary basal body

in interphase
Comment Inversin was shown to localize to different subcellular locations, in a cell cycle-dependent manner. It is found at the mitotic spindle in mitosis, at the mid-body in cytokinesis, and in cilia at the basal body and centrosome in interphase. All of these subcellular organelles are involved in regulation of planar cell polarity or the cell cycle.
Formal Description
Interaction-ID: 70119

gene/protein

INVS

is localized in

cellular component

centrosome

in interphase
Comment When inversin is defective (as in NPHP type 2), canonical Wnt pathway will prevail and disrupt the apical-basolateral polarity of renal epithelium.
Formal Description
Interaction-ID: 70120

gene/protein mutant

INVS-mut

increases_activity of

Comment When inversin is defective (as in NPHP type 2), canonical Wnt pathway will prevail and disrupt the apical-basolateral polarity of renal epithelium.
Formal Description
Interaction-ID: 70121
Comment Mutations in NPHP3 are responsible for adolescent nephronophthisis in a large Venezuelan kindred. Nphp3 cause the renal cystic mouse mutant pcy, which was demonstrated to be responsive to treatment with a vasopressin receptor antagonist. Truncating mutations of NPHP3 in humans causes a broad clinical spectrum of early embryonic patterning defects that resembles Meckel syndrome. This includes situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulae, and a wide range of congenital anomalies of the kidney and urinary tract.
Formal Description
Interaction-ID: 70122

gene/protein mutant

NPHP3-mut

increases_activity of

Comment Mutations in NPHP3 are responsible for adolescent nephronophthisis in a large Venezuelan kindred. Nphp3 cause the renal cystic mouse mutant pcy, which was demonstrated to be responsive to treatment with a vasopressin receptor antagonist. Truncating mutations of NPHP3 in humans causes a broad clinical spectrum of early embryonic patterning defects that resembles Meckel syndrome. This includes situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulae, and a wide range of congenital anomalies of the kidney and urinary tract.
Formal Description
Interaction-ID: 70123

gene/protein mutant

NPHP3-mut

increases_activity of

Comment Nephrocystin-4, like inversin, localizes to primary cilia, basal bodies, centrosomes, and the cortical actin cytoskeleton.
Formal Description
Interaction-ID: 70124

gene/protein

NPHP4

is localized in

cellular component

cilium

Comment Nephrocystin-4, like inversin, localizes to primary cilia, basal bodies, centrosomes, and the cortical actin cytoskeleton.
Formal Description
Interaction-ID: 70125

gene/protein

NPHP4

is localized in

cellular component

ciliary basal body

Comment Nephrocystin-4, like inversin, localizes to primary cilia, basal bodies, centrosomes, and the cortical actin cytoskeleton.
Formal Description
Interaction-ID: 70126

gene/protein

NPHP4

is localized in

cellular component

centrosome

Comment Nephrocystin-4, like inversin, localizes to primary cilia, basal bodies, centrosomes, and the cortical actin cytoskeleton.
Formal Description
Interaction-ID: 70127

gene/protein

NPHP4

is localized in

cellular component

cortical actin cytoskeleton

Comment When the novel gene NPHP5 (IQCB1, SLSN5) was identified as mutated in nephronophthisis type 5, all mutations detected were truncations of the encoded protein nephrocystin-5, and all patients had early-onset retinitis pigmentosa (Senior-Løken syndrome).
Formal Description
Interaction-ID: 70128

gene/protein mutant

IQCB1-mut

increases_activity of

disease

Nephronophthisis 5

Comment When the novel gene NPHP5 (IQCB1, SLSN5) was identified as mutated in nephronophthisis type 5, all mutations detected were truncations of the encoded protein nephrocystin-5, and all patients had early-onset retinitis pigmentosa (Senior-Løken syndrome).
Formal Description
Interaction-ID: 70129

gene/protein mutant

IQCB1-mut

increases_activity of

Comment Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin, and is in a complex with the retinitis pigmentosa GTPase regulator (RPGR), which when defective causes X-linked retinitis pigmentosa. Both nephrocystin-5 and RPGR are localized in connecting cilia of photoreceptors and in primary cilia of renal epithelial cells. That connecting cilia of photoreceptors are the structural equivalents of primary cilia of renal epithelial cells renders an explanation for retinal involvement in the retinal-renal syndrome Senior-Loken syndrome.
Formal Description
Interaction-ID: 70130

gene/protein

IQCB1

interacts (colocalizes) with

gene/protein

CALM

Comment Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin, and is in a complex with the retinitis pigmentosa GTPase regulator (RPGR), which when defective causes X-linked retinitis pigmentosa. Both nephrocystin-5 and RPGR are localized in connecting cilia of photoreceptors and in primary cilia of renal epithelial cells. That connecting cilia of photoreceptors are the structural equivalents of primary cilia of renal epithelial cells renders an explanation for retinal involvement in the retinal-renal syndrome Senior-Loken syndrome.
Formal Description
Interaction-ID: 70131

gene/protein

IQCB1

interacts (colocalizes) with

gene/protein

RPGR

Comment Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin, and is in a complex with the retinitis pigmentosa GTPase regulator (RPGR), which when defective causes X-linked retinitis pigmentosa. Both nephrocystin-5 and RPGR are localized in connecting cilia of photoreceptors and in primary cilia of renal epithelial cells. That connecting cilia of photoreceptors are the structural equivalents of primary cilia of renal epithelial cells renders an explanation for retinal involvement in the retinal-renal syndrome Senior-Loken syndrome.
Formal Description
Interaction-ID: 70132

gene/protein

IQCB1

is localized in

cellular component

cilium

in renal epithelial cells
Comment Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin, and is in a complex with the retinitis pigmentosa GTPase regulator (RPGR), which when defective causes X-linked retinitis pigmentosa. Both nephrocystin-5 and RPGR are localized in connecting cilia of photoreceptors and in primary cilia of renal epithelial cells. That connecting cilia of photoreceptors are the structural equivalents of primary cilia of renal epithelial cells renders an explanation for retinal involvement in the retinal-renal syndrome Senior-Loken syndrome.
Formal Description
Interaction-ID: 70133

gene/protein

IQCB1

is localized in

cellular component

photoreceptor connecting cilium

in photoreceptors
Comment Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin, and is in a complex with the retinitis pigmentosa GTPase regulator (RPGR), which when defective causes X-linked retinitis pigmentosa. Both nephrocystin-5 and RPGR are localized in connecting cilia of photoreceptors and in primary cilia of renal epithelial cells. That connecting cilia of photoreceptors are the structural equivalents of primary cilia of renal epithelial cells renders an explanation for retinal involvement in the retinal-renal syndrome Senior-Loken syndrome.
Formal Description
Interaction-ID: 70134

gene/protein

RPGR

is localized in

cellular component

cilium

in renal epithelial cells
Comment Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin, and is in a complex with the retinitis pigmentosa GTPase regulator (RPGR), which when defective causes X-linked retinitis pigmentosa. Both nephrocystin-5 and RPGR are localized in connecting cilia of photoreceptors and in primary cilia of renal epithelial cells. That connecting cilia of photoreceptors are the structural equivalents of primary cilia of renal epithelial cells renders an explanation for retinal involvement in the retinal-renal syndrome Senior-Loken syndrome.
Formal Description
Interaction-ID: 70135

gene/protein

RPGR

is localized in

cellular component

photoreceptor connecting cilium

in photoreceptors
Comment Truncating mutations in a novel gene NPHP6/CEP290 were identified as the cause of NPHP type 6 and Joubert syndrome type 5.
Formal Description
Interaction-ID: 70136

gene/protein mutant

CEP290-mut

increases_activity of

disease

Nephronophthisis 6

Comment Truncating mutations in a novel gene NPHP6/CEP290 were identified as the cause of NPHP type 6 and Joubert syndrome type 5.
Formal Description
Interaction-ID: 70137

gene/protein mutant

CEP290-mut

increases_activity of

Comment The gene product nephrocystin-6/Cep290 is part of the centrosomal proteome.
Formal Description
Interaction-ID: 70138

gene/protein

CEP290

is localized in

cellular component

centrosome

Comment Like NPHP2/inversin and NPHP4, NPHP6/CEP290 is expressed in centrosomes and the mitotic spindle in a cell cycle-dependent manner.
Formal Description
Interaction-ID: 70139

gene/protein

CEP290

is localized in

cellular component

mitotic spindle

Comment Nephrocystin-6 modulates the activity of ATF4/CREB2, a transcription factor implicated in cAMP-dependent renal cyst formation.
Formal Description
Interaction-ID: 70140

gene/protein

CEP290

affects_activity of

gene/protein

ATF4

Comment A 300-amino acid in-frame deletion of NPHP6/CEP290 causes retinal degeneration only, without renal or cerebellar involvement in the rds16 mouse model. This is in accordance with the finding that a hypomorphic mutation of Nphp6/Cep290 represents the most frequent cause of Leber’s congenital amaurosis. Mutations in NPHP6/CEP290 have been confirmed as causing Joubert syndrome with and without renal involvement. Furthermore, truncating mutations in NPHP6 were shown to cause Meckel-Gruber syndrome.
Formal Description
Interaction-ID: 70141

gene/protein mutant

CEP290-mut

increases_activity of

Comment A 300-amino acid in-frame deletion of NPHP6/CEP290 causes retinal degeneration only, without renal or cerebellar involvement in the rds16 mouse model. This is in accordance with the finding that a hypomorphic mutation of Nphp6/Cep290 represents the most frequent cause of Leber’s congenital amaurosis. Mutations in NPHP6/CEP290 have been confirmed as causing Joubert syndrome with and without renal involvement. Furthermore, truncating mutations in NPHP6 were shown to cause Meckel-Gruber syndrome.
Formal Description
Interaction-ID: 70142

gene/protein mutant

CEP290-mut

increases_activity of

Comment Mutations in the gene NPHP7/GLIS2 in a Cree Indian kindred encoding the transcription factor Gli-similar protein 2 were identified as the cause of NPHP type 7. Starting at 8 wk of age, Glis2 mutant mice show severe renal atrophy and fibrosis resembling human nephronophthisis.
Formal Description
Interaction-ID: 70143

gene/protein mutant

GLIS2-mut

increases_activity of

Comment Differential gene expression studies on Glis2 mutant kidneys demonstrated that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2.
Formal Description
Interaction-ID: 70144

gene/protein

GLIS2

affects_activity of

Comment GLIS2 is related to the GLI transcription factor, and these findings implicate the hedgehog pathway in the pathogenesis of cystic kidney diseases. It is a signaling pathway that controls cell determination and tissue patterning during embryogenesis. The other known role of hedgehog is the maintenance of stem cell pools in postembryonic tissues.
Formal Description
Interaction-ID: 70145

gene/protein

GLIS2

affects_activity of

Comment Missense and truncating mutations in the NPHP8/RPGRIP1L gene were identified by positional cloning as the cause of a Joubert syndrome-like phenotype (cerebrooculo-renal syndrome [CORS]) and Meckel syndrome.
Formal Description
Interaction-ID: 70146

gene/protein mutant

RPGRIP1L-mut

increases_activity of

disease

Nephronophthisis 8

Comment Missense and truncating mutations in the NPHP8/RPGRIP1L gene were identified by positional cloning as the cause of a Joubert syndrome-like phenotype (cerebrooculo-renal syndrome [CORS]) and Meckel syndrome.
Formal Description
Interaction-ID: 70147

gene/protein mutant

RPGRIP1L-mut

increases_activity of

Comment Missense and truncating mutations in the NPHP8/RPGRIP1L gene were identified by positional cloning as the cause of a Joubert syndrome-like phenotype (cerebrooculo-renal syndrome [CORS]) and Meckel syndrome.
Formal Description
Interaction-ID: 70148

gene/protein mutant

RPGRIP1L-mut

increases_activity of

Comment Missense and truncating mutations in the NPHP8/RPGRIP1L gene were identified by positional cloning as the cause of a Joubert syndrome-like phenotype (cerebrooculo-renal syndrome [CORS]) and Meckel syndrome.
Formal Description
Interaction-ID: 70149

gene/protein mutant

RPGRIP1L-mut

increases_activity of

disease

Cerebrooculo-renal syndrome, type 3

Comment RPGRIP1L co-localizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4. RPGRIP1L missense mutations found in individuals with CORS diminish the interaction between RPGRIP1L and nephrocystin-4.
Formal Description
Interaction-ID: 70150

gene/protein

RPGRIP1L

interacts (colocalizes) with

gene/protein

CEP290

at the basal body, at the centrosomes
Comment RPGRIP1L co-localizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4. RPGRIP1L missense mutations found in individuals with CORS diminish the interaction between RPGRIP1L and nephrocystin-4.
Formal Description
Interaction-ID: 70151

gene/protein

RPGRIP1L

interacts (colocalizes) with

gene/protein

NPHP4

at the basal body, at the centrosomes
Comment Three different highly conserved amino acid changes in the gene NEK8 (never in mitosis kinase 8) as causing NPHP type 9. One of the mutations identified is positioned in the same RCC1 domain in which a missense mutation causes renal cystic disease in jck mice. Upon expression in medullary collecting duct cells, all three mutant forms of NEK8 showed defects in ciliary and centrosomal localization to varying degrees, supporting the notion that mutations in NEK8 cause NPHP type 9.
Formal Description
Interaction-ID: 70152

gene/protein mutant

NEK8-mut

increases_activity of

Comment NEK8 plays a major role in cell-cycle regulation, this provides a direct link between a protein defective in renal cystic disease and the role of centrosomes for cell-cycle regulation.
Formal Description
Interaction-ID: 70153

gene/protein

NEK8

increases_activity of

Comment Cilia consist of a microtubule-based axoneme covered by a specialized plasma membrane. The axoneme has nine peripheral microtubule doublets. There may be two central microtubules (9 + 2 versus 9 + 0 axoneme). 9 + 2 cilia usually have dynein arms that link the microtubule doublets and are motile, whereas most 9 + 0 cilia lack dynein arms and are nonmotile (“primary cilia”) with a few exceptions.
Formal Description
Interaction-ID: 70154

cellular component

axoneme

is localized in

cellular component

cilium

Comment Cilia consist of a microtubule-based axoneme covered by a specialized plasma membrane. The axoneme has nine peripheral microtubule doublets. There may be two central microtubules (9 + 2 versus 9 + 0 axoneme). 9 + 2 cilia usually have dynein arms that link the microtubule doublets and are motile, whereas most 9 + 0 cilia lack dynein arms and are nonmotile (“primary cilia”) with a few exceptions.
Formal Description
Interaction-ID: 70155

cellular component

axoneme

is localized in

cellular component

motile cilium

Comment Cilia consist of a microtubule-based axoneme covered by a specialized plasma membrane. The axoneme has nine peripheral microtubule doublets. There may be two central microtubules (9 + 2 versus 9 + 0 axoneme). 9 + 2 cilia usually have dynein arms that link the microtubule doublets and are motile, whereas most 9 + 0 cilia lack dynein arms and are nonmotile (“primary cilia”) with a few exceptions.
Formal Description
Interaction-ID: 70156

cellular component

microtubule

is localized in

cellular component

axoneme

Comment The ciliary axoneme is anchored in the basal body, a microtubule-organizing center derived from the mother centriole.
Formal Description
Interaction-ID: 70157

cellular component

axoneme

interacts (colocalizes) with

cellular component

ciliary basal body

Comment The transition zone at the junction of the basal body acts as a filter for the molecules that can pass into or out of the cilium.
Formal Description
Interaction-ID: 70158

cellular component

ciliary transition zone

affects_activity of

Comment GLIS2/NPHP7 is localized in the primary cilium.
Formal Description
Interaction-ID: 70159

gene/protein

GLIS2

is localized in

cellular component

cilium

Comment Inversin/NPHP2 mediates a switch from the canonical the non-canonical Wnt signaling pathway, which plays a role in planar cell polarity maintenance.
Formal Description
Interaction-ID: 70160

gene/protein

INVS

decreases_activity of

Comment Inversin/NPHP2 mediates a switch from the canonical the non-canonical Wnt signaling pathway, which plays a role in planar cell polarity maintenance.
Formal Description
Interaction-ID: 70161

gene/protein

INVS

increases_activity of