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FLASH GENE

Symbol

NPHS1

contributors: mct/pgu - updated : 20-11-2015

HGNC name	nephrosis 1, congenital, Finnish type (nephrin)
HGNC id	7908

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine pancreas islet of Langerhans     highly Homo sapiens Lymphoid/Immune thymus       moderately Homo sapiens Urinary kidney nephron renal capsule glomerulus highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Homo sapiens Endocrine islet cell (alpha,beta...) Homo sapiens Urinary podocyte

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	kidney
	expressed in the epicardium and coronary vessels during embryonic development

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	eight Ig-like C2-type motifs
	a fibronectin type III-like motif
	a transmembrane segment
	a intracellular domain connected indirectly to the actin cytoskeleton
	a C-terminal short 154 AA cytoplasmic tail containing eight tyrosines , with a class 1 PDZ-binding motif, important for XPR1/KIRREL functions, having several putative tyrosine phosphorylation sites that can be phosphorylated by the Src kinase FYN

conjugated

GlycoP

HOMOLOGY

interspecies	homolog to rattus Nphs1 (82.3 pc)
	homolog to murine Nphs1 (82.6 pc)

Homologene

FAMILY

immunoglobulin superfamily

CATEGORY

adhesion , receptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,endoplasmic reticulum
text	single-pass type I membrane protein
	specifically located at the split membrane extending between foot processes of the podocytes

basic FUNCTION	signaling cell-cell adhesion protein
	mediating filtration through the podocyte filter which sits at the interface of the capillary and the nephron
	playing a role in the development or function of the kidney glomerular filtration barrier
	may anchor the podocyte slit diaphragm to the actin cytoskeleton
	cooperates with KIRREL to transduce a signal that induces actin polymerization
	plays a role in organizing the surface expression of ion channel proteins in podocytes and may play a role in outside-in signaling to allow podocytes to adapt to mechanical or neurohumoral stimuli originating in neighboring cells
	playing a role in vesicular docking and insulin responsiveness of podocytes
	may be playing a role in secondary fusion of myoblasts into nascent myotubes
	transduces a phosphotyrosine signal through its cytoplasmic domain, which contains several putative tyrosine phosphorylation sites for Src-family kinases such as FYN
	with KIRREL2 could interact homophilically and heterophilically, suggesting that NPHS1 and KIRREL2 might regulate certain developmental aspects of PTF1A-positive neurons as homo- or heterooligomers
	nephrin and KIRREL are essential components of the slit diaphragm
	nephrin and KIRREL or KIRREL2 trans-interactions promote cell-contact formation, suggesting that they may also function together in slit diaphragm assembly
	KIRREL and NPHS1 organize a signaling complex at the podocyte cell membrane that forms the structural framework for a functional glomerular filtration barrier
	not only has a function in kidney podocytes, but is also required for cardiovascular development
	serves a crucial function in cardiac vessel development
	NPHS1 and NGFR share a partial overlapping expression pattern in the epicardium and subepicardial coronary vessels
	not only initiates actin polymerization but also assembles a protein complex that is necessary to regulate the architecture of the generated actin filament network and focal adhesion dynamics
	key component of the kidney slit diaphragm that contributes to the morphology of podocyte foot processes through signaling to the underlying actin cytoskeleton
	dynamic molecular link between nephrin signaling and the canonical Hippo pathway in podocytes, which may facilitate the conversion of mechanical cues to biochemical signals promoting podocyte viability

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

excretion

text

urologic

PATHWAY

metabolism

signaling

JNK cascade

a component	complexing with NPHS2
	major component of the slit membrane of the glomerular podocytes
	part of a complex network of proteins that are necessary for the structural and signaling integrity of the podocyte slit diaphragm
	KIRREL2 homodimerizes and heterodimerizes with nephrin and KIRREL

INTERACTION

DNA

RNA

small molecule

protein	interacting with CD2AP C-terminal domain
	interacting with IQGAP1
	interacting with podocin/NPHS2 and KIRREL
	interacting with NPHP1 and PARD3 (interaction mediated through the PDZ domain of PARD3 and conserved carboxyl terminal residues in NPHP1 and NPHS1, essential for establishing the three-dimensional architecture of podocytes at the kidney filtration barrier)
	binds to the C-terminus of a large-conductance Ca2+-activated K+ channel isoform (KCNMA1) and regulates its expression on the cell surface
	PTF1A directly controls expression of immunoglobulin superfamily molecules NPHS1, and KIRREL2 in the developing central nervous system
	interaction between KIRREL, KIRREL3 and NPHS1
	PRKCA and PICK1 are NPHS1-binding proteins
	directly interacts with NGFR and reveal an important role for nephrin in murine cardiac development by permitting survival of cardiovascular progenitor cells
	similarly to KIRREL, MYO1C also binds NPHS1 and reduces its localization at the podocyte cell membrane
	recruits and regulates a protein complex that includes INPPL1, FLNA and RAPH1, proteins important in regulation of actin and focal adhesion dynamics, as well as lamellipodia formation
	SIRPA interacts with NPHS1 at the slit diaphragm, and its phosphorylation is dynamically regulated in proteinuric states
	SEPT7 associates with CD2AP and NPHS1, both essential for glomerular ultrafiltration
	NCK1 directly modulates NPHS1 phosphorylation through formation of a signaling complex with the Src family kinase FYN
	NCK1 integrates NPHS1 with the Hippo kinase cascade through association with the adaptor protein WTIP

cell & other

REGULATION

activated by

activation of PPARA in embryonic kidney epithelial cells and podocytes by a dual mechanism

repressed by

phosphorylated on tyrosine residues

ASSOCIATED DISORDERS

corresponding disease(s)

NPHS1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   downregulated in patients with proteinuric glomerular diseases

Susceptibility

to minimal change nephrotic syndrome

Variant & Polymorphism other	variants C265R and V822M associated to minimal change nephrotic syndrome

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

murine Nphs1, expressed in kidney, brain, pancreas, knockout leading to massive proteinuria and neonatal death