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FLASH GENE

Symbol

SCNN1A

contributors: mct/npt - updated : 21-06-2023

HGNC name	sodium channel, nonvoltage-gated 1 alpha
HGNC id	10599

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	BESC2 bronchiectasis with or without elevated sweat chloride 2 PHA1B pseudohypoaldosteronism, type 1 B
Location	12p13.31      Physical location : 6.456.010 - 6.486.523
Synonym name	sodium channel epithelial, alpha subunit
	epithelial Na(+) channel subunit alpha
	amiloride-sensitive epithelial sodium channel alpha subunit
	nasal epithelial sodium channel alpha subunit
Synonym symbol(s)	SCNL, ENACA, SCNN1, SCNEA, ENaCalpha, Alpha-NaCH, ENaCa, FLJ21883, ENAC

DNA

TYPE	functioning gene
STRUCTURE	30.51 kb     13 Exon(s)

10 Kb 5' upstream gene genomic sequence study

motif	repetitive sequence   ALU
text structure	eight alu sequences

MAPPING

cloned

Y

linked

status

confirmed

Map	pter - D12S372 - D12S314 - [D12S93 - CD4 - SCNN1A ,D12S374 - D12S356 ] - D12S77 - D12S89 ,D12S96 - cen
Authors	Strautnieks (96)

RNA

TRANSCRIPTS	type	messenger

text	a splice variant with an Alu cassette in 3'UTR

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001159576 12 - 3497 NP_001153048 - 728 - 2009 19462466 NM_001038 13 - 3345 NP_001029 - 669 - 2009 19462466 NM_001159575 13 - 3216 NP_001153047 - 692 - 2009 19462466

EXPRESSION

Type

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         Hearing/Equilibrium ear middle       Homo sapiens Reproductive male system prostate       Respiratory lung       highly Homo sapiens urinary kidney nephron distal convoluted tubule     Urinary kidney tubule collecting duct   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol Hearing / Equilibrium epithelial cell Homo sapiens Respiratory alveolar cell type II Homo sapiens Respiratory epithelial cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	(at least) two membrane spanning segments, several glycosylation and a nucleotide binding sites
	a N terminal cluster of negatively charged AA forming a cytoslic domain reactive at the plasma
	a C terminal cluster of positively charged AA forming a cytosolic domain reactive at the plasma, including a PPxY motif of interaction with the WW motif of NEDD4, C terminus shown to be important for channel modulation by the actin cytoskeleton

mono polymer

heteromer , tetramer

HOMOLOGY

Homologene

FAMILY

degenerin/ENaC superfamily of non-voltage-gated, highly amiloride-sensitive cation channels

CATEGORY

transport channel

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
text	luminal membrane of the collecting tubule of kidney, (NHE4-PEN), apical membrane

basic FUNCTION	controlling the reabsorption of sodium in kidney, colon, lung and sweat glands
	playing a role in taste perception
	assembly and targeting of an active chanel to the surface of the cell
	plays a key role in salt homoeostasis and in regulating blood pressure (Wiemuth 2007)
	multi-ubiquitinated at the cell surface (Wiemuth 2007)
	plays an important role in fluid absorption in the endolymphatic sac and its function may be altered during inflammatory conditions (Kim 2009)
	key player in the maintenance of whole body Na(+) balance, and consequently of blood pressure (pMID: 21084303)
	its function also regulates extracellular fluid volume as water flows across membranes accompanying Na(+) ions to maintain osmolarity
	on motile cilia should be essential for diverse functions of motile cilia, such as germ cell transport, fertilization, implantation, clearance of respiratory airways and cell migration
	is not a passive passenger in regulated epithelial vesicle trafficking, but plays a role in establishing and maintaining the pool of vesicles that respond to cAMP stimulation
	in the kidneys is critical for Na+ balance, extracellular volume, and blood pressure
	cell-specific SCNN1A is important in propagating pulsatility into the renal circulation, generating oxidant stress, reduced bioavailable nitric oxide (NO), and renal vessel wall fibrosis and stiffening
	is a novel regulator of breast cancer cell proliferation

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

component of a heterotetramer including two SCNN1A, one SCNN1B and one SCNN1G

INTERACTION

DNA

RNA

small molecule

protein	NEDD4
	SCNN1A and CFTR physically associate in mammalian cells (limiting proteolytic cleavage of SCNN1A is a mechanism by which CFTR down-regulates Na+ absorption)
	PCSK9 inhibits ENaC (SCNN1A, SCNN1B, SCNN1G) current by reducing the number of channels at the cell surface
	CNKSR3 physically interacts with SCNN1A, B, D, NEDD4L, and SGK1 and stimulates SCNN1A, SCNN1B, SCNN1D function in a PDZ domain-dependent, aldosterone-induced manner
	FLNA reduces SCNN1A channel function through direct interaction on the cell surface
	role for USP8 in the control of SCNN1A ubiquitination and trafficking
	NEDD8 plays an important role in the ubiquitination of SCNN1A in alveolar epithelial cells
	COMMD3 and COMMD9 may be endogenous regulators of SCNN1A to regulate Na&
	8314; transport through altering SCNN1A cell surface expression
	PRSS8 is a regulator of SCNN1A in colon
	CALM1 and CAMK2A modulate SCNN1A activity by destabilizing the association between the actin cytoskeleton, SCNN1A, and MARCKS, or MARCKSL1 at the apical membrane
	DERL1 promotes SCNN1A ubiquitylation and enhances SCNN1A ubiquitin- mediated proteasome degradation
	CLDN7 plays an important role in salt balance in renal collecting duct (CD) cells and modulating WNK4 and SCNN1A expression levels that are vital in controlling salt-sensitive hypertension

cell & other

REGULATION

inhibited by

NEDD4L (major inactivating enzyme for SCNN1A in urinary tubular cells) (Araki 2009)

Other	regulated by aldosterone
	regulated by CFTR (CFTR stabilizes SCNN1A at the plasma membrane, suggesting that CFTR regulates its stability)(Lu 2007)
	the ubiquitination state of SCNN1A is critical for the regulation of epithelial Na(+) absorption
	K+ channels regulate SCNN1A expression by controlling its promoter activity and thus affect the alveolar function of fluid clearance

ASSOCIATED DISORDERS

corresponding disease(s)

PHA1B , BESC2

Susceptibility

HTA and proteinuria

Variant & Polymorphism SNP	A(2139)G, A to G

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer reproductive breast is a potential future therapeutic target in breast cancer

ANIMAL & CELL MODELS