PIEZO2

Summary

PIEZO2 (piezo type mechanosensitive ion channel component 2, HGNC:26270) is a protein-coding gene on chromosome 18p11.22-p11.21, encoding Piezo-type mechanosensitive ion channel component 2 (Q9H5I5). Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain.

The protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels. These channels serve to connect mechanical forces to biological signals. The encoded protein quickly adapts MA currents in somatosensory neurons. Defects in this gene are a cause of type 5 distal arthrogryposis. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.

Source: NCBI Gene 63895 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arthrogryposis, distal, with impaired proprioception and touch (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 1,445 total — 62 pathogenic, 63 likely-pathogenic
• Phenotypes (HPO): 175
• MANE Select transcript: NM_001378183

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26270
Approved symbol	PIEZO2
Name	piezo type mechanosensitive ion channel component 2
Location	18p11.22-p11.21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23403, FLJ23144, HsT748, HsT771, FLJ34907
Ensembl gene	ENSG00000154864
Ensembl biotype	protein_coding
OMIM	613629
Entrez	63895

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 8 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000302079, ENST00000383408, ENST00000503781, ENST00000538948, ENST00000578145, ENST00000579112, ENST00000579151, ENST00000579899, ENST00000579949, ENST00000580640, ENST00000581680, ENST00000582913, ENST00000582937, ENST00000583325, ENST00000643712, ENST00000674853, ENST00000685517, ENST00000686869, ENST00000688929, ENST00000691469, ENST00000693743

RefSeq mRNA: 3 — MANE Select: NM_001378183 NM_001378183, NM_001410871, NM_022068

CCDS: CCDS11850, CCDS92435, CCDS92436

Canonical transcript exons

ENST00000674853 — 56 exons

Exon	Start	End
ENSE00001018194	10857001	10857211
ENSE00001111048	10855353	10855566
ENSE00001163259	10807112	10807274
ENSE00001184001	10797374	10797522
ENSE00001184006	10800337	10800475
ENSE00001184010	10803875	10803994
ENSE00001184045	10759482	10759583
ENSE00001184051	10759705	10759909
ENSE00001184058	10760911	10761111
ENSE00001184066	10762500	10762625
ENSE00001184080	10762922	10763098
ENSE00001283817	10801390	10801428
ENSE00001286051	10770148	10770308
ENSE00001286059	10773412	10773629
ENSE00001286064	10774006	10774038
ENSE00001286070	10780325	10780366
ENSE00001286075	10784784	10784957
ENSE00001411604	10794772	10795002
ENSE00002269737	10911186	10911228
ENSE00002270003	10787036	10787184
ENSE00002272763	10979535	10979660
ENSE00002303866	11066127	11066222
ENSE00003461890	10715650	10715816
ENSE00003480241	10704394	10704652
ENSE00003480887	10701989	10702171
ENSE00003492997	10791201	10791324
ENSE00003494154	10697748	10697880
ENSE00003499937	10696392	10696539
ENSE00003503802	10705336	10705746
ENSE00003511599	10741031	10741102
ENSE00003524632	10672690	10672873
ENSE00003540092	10789079	10789365
ENSE00003549734	10681661	10681753
ENSE00003555484	10736604	10736710
ENSE00003577942	10714764	10714930
ENSE00003584668	10675209	10675288
ENSE00003587542	10680199	10680371
ENSE00003592021	10718200	10718259
ENSE00003614146	10871253	10871415
ENSE00003616530	10696074	10696288
ENSE00003663770	10682104	10682292
ENSE00003672398	10677747	10677875
ENSE00003676374	10698925	10699177
ENSE00003677775	10731407	10731521
ENSE00003688817	10689655	10689802
ENSE00003691399	10691225	10691383
ENSE00003710058	10742494	10742615
ENSE00003718201	10757969	10758134
ENSE00003718615	10750091	10750187
ENSE00003731742	10748471	10748630
ENSE00003743148	10752636	10752879
ENSE00003749768	10744142	10744231
ENSE00003821711	10708275	10708439
ENSE00003899335	10735232	10735330
ENSE00003900582	11148525	11149569
ENSE00003903018	10670247	10671779

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 97.57.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6775 / max 108.5483, expressed in 676 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171205	3.6415	675
171202	0.0360	10

Top tissues by expression

282 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.57	gold quality
corpus callosum	UBERON:0002336	91.06	gold quality
dorsal root ganglion	UBERON:0000044	88.33	gold quality
visceral pleura	UBERON:0002401	87.29	gold quality
inferior vagus X ganglion	UBERON:0005363	87.26	gold quality
trigeminal ganglion	UBERON:0001675	87.05	gold quality
adrenal tissue	UBERON:0018303	86.45	gold quality
pleura	UBERON:0000977	85.60	gold quality
parietal pleura	UBERON:0002400	85.21	gold quality
cranial nerve II	UBERON:0000941	85.13	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.98	gold quality
calcaneal tendon	UBERON:0003701	84.00	gold quality
spinal cord	UBERON:0002240	83.99	gold quality
inferior olivary complex	UBERON:0002127	83.80	gold quality
lower lobe of lung	UBERON:0008949	82.86	silver quality
colonic epithelium	UBERON:0000397	82.47	gold quality
lung	UBERON:0002048	81.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.04	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	80.31	gold quality
subthalamic nucleus	UBERON:0001906	80.17	gold quality
globus pallidus	UBERON:0001875	79.92	gold quality
CA1 field of hippocampus	UBERON:0003881	79.83	gold quality
Brodmann (1909) area 46	UBERON:0006483	79.47	gold quality
substantia nigra	UBERON:0002038	79.43	gold quality
medial globus pallidus	UBERON:0002477	79.43	gold quality
upper lobe of lung	UBERON:0008948	79.34	gold quality
midbrain	UBERON:0001891	78.94	gold quality
cartilage tissue	UBERON:0002418	78.92	gold quality
upper lobe of left lung	UBERON:0008952	78.82	gold quality
right lung	UBERON:0002167	78.66	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	590.48
E-CURD-119	yes	11.33
E-MTAB-9067	yes	7.32
E-ANND-3	yes	7.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting PIEZO2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-129-5P	99.88	70.26	3273

Literature-anchored findings (GeneRIF, showing 40)

• piezo2 sensitization may contribute to PKA- and PKC-mediated mechanical hyperalgesia. (PMID:22921401)
• Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. (PMID:23487782)
• this study used exome sequencing to discover that mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. (PMID:24726473)
• family of mechanically activated channels that counts only two members in human, piezo1 and 2, has emerged recently. [review] (PMID:25037583)
• we demonstrate that the mechanosensitivity of human embryonic stem cell-derived touch receptors depends on PIEZO2 (PMID:25469543)
• Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. (PMID:25712306)
• Transgenic mouse lines lacking Piezo2 in proprioceptive neurons showed severely uncoordinated body movements. (PMID:26551544)
• Enterochromaffin cells in the human and mouse small bowel GI epithelium selectively express the mechanosensitive ion channel Piezo2, and also that activation of Piezo2 by force leads to inward currents, 5-HT release and an increase in mucosal secretion (PMID:27392819)
• we report a consanguineous family with three siblings who showed short stature, scoliosis, gross motor impairment, and a progressive form of contractures involving the distal joints that is distinct from that found in patients with domina Recessive mutations in PIEZO2 thus appear to cause a progressive phenotype that overlaps with, while being mostly distinct from that associated with dominant mutations in the same gene (PMID:27607563)
• Our results show that PIEZO2 is a determinant of mechanosensation in humans. (PMID:27653382)
• we report the developmental phenotypic spectrum of familial Gordon syndrome in one family due to the previously characterized PIEZO2 mutation c.8057G>A. (PMID:27714920)
• The Piezo2 convert a variety of mechanical stimuli into channel activation and subsequent inactivation, and what molecules and mechanisms modulate Piezo function. (PMID:27743844)
• We identified homozygous loss of function variants in PIEZO2 as the underlying cause for an autosomal-recessive distal muscular atrophy with arthrogryposis, kyphoscoliosis, and neonatal respiratory insufficiency distinct from previously described dominant PIEZO2 diseases. (PMID:27843126)
• Sensory ataxia and proprioception defect with dorsal column involvement together with arthrogryposis, myopathy, scoliosis and progressive respiratory failure may represent a distinct clinical phenotype, and indicate recessive mutations in PIEZO2 (PMID:27974811)
• The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner’s corpuscles) low-threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch (PMID:28905996)
• Study demonstrate the splicing of Piezo2 to be cell type specific. Biophysical characterization revealed substantial differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants. (PMID:29212024)
• This study identified Piezo2 mechanosensitive cationic channel as a transducer of environmental physical cues into mechanobiological responses. (PMID:29432180)
• The molecular defects identified through clinical exome sequencing in this study expands the phenotypic spectra of CHD7-associated disorders and implicate PIEZO2 as a candidate gene for major eye developmental defects. (PMID:30181649)
• Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) 2B and mild DA in two Chinese families. (PMID:30285720)
• individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. (PMID:30305456)
• the presence of both Piezo1 and 2 in enteric neurons throughout the gastrointestinal tract from guinea pigs, mice and humans, were studied. (PMID:30324494)
• identify a functionally conserved inactivation gate in the pore-lining inner helix of mouse Piezo1 and Piezo2 that is distinct from the two constrictions (PMID:30628892)
• Results indicate the critical prognostic values of the piezo type mechanosensitive ion channel components PIEZO1 and PIEZO2 in non-small cell lung cancer (NSCLC). (PMID:30745454)
• we present a 3-generation family affected with DA5, who all carry a variant of unknown clinical significance c.8068A>C (p.Ser2690Arg) in the PIEZO2 gene. DA5 is a very rare condition with less than 20 cases previously reported. Our report expands the phenotype and contributes to evidence of this variant’s pathogenicity. (PMID:30938034)
• The Piezo2 ion channel is mechanically activated by low-threshold positive pressure. (PMID:31015490)
• Studied role of piezo type mechanosensitive ion channel component 2 (PIEZO2) expression in development of adolescent idiopathic scoliosis. (PMID:31513102)
• A neuromuscular disorder with homozygosity for PIEZO2 gene variants: an important differential diagnosis for kyphoscoliotic Ehlers-Danlos Syndrome. (PMID:31609726)
• A dietary fatty acid counteracts neuronal mechanical sensitization. (PMID:32561714)
• Glans clitoris innervation: PIEZO2 and sexual mechanosensitivity. (PMID:32996126)
• PIEZO2 in sensory neurons and urothelial cells coordinates urination. (PMID:33057202)
• Confirming the involvement of PIEZO2 in the etiology of Marden-Walker syndrome. (PMID:33369052)
• The Form and Function of PIEZO2. (PMID:34153212)
• Piezo2 downregulation via the Cre-lox system affects aqueous humor dynamics in mice. (PMID:34220183)
• Molecular Sensors of Temperature, Pressure, and Pain with Special Focus on TRPV1, TRPM8, and PIEZO2 Ion Channels. (PMID:34825354)
• Is the Sex Difference a Clue to the Pathomechanism of Dry Eye Disease? Watch out for the NGF-TrkA-Piezo2 Signaling Axis and the Piezo2 Channelopathy. (PMID:35507012)
• Piezo2 is not an indispensable mechanosensor in murine cardiomyocytes. (PMID:35581325)
• PIEZO2 ion channels in proprioception. (PMID:35689908)
• Distal Arthrogryposis type 5 in an Italian family due to an autosomal dominant gain-of-function mutation of the PIEZO2 gene. (PMID:35906671)
• Loss of lung microvascular endothelial Piezo2 expression impairs NO synthesis, induces EndMT, and is associated with pulmonary hypertension. (PMID:36149769)
• The role of PIEZO ion channels in the musculoskeletal system. (PMID:36717101)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	piezo2a.2	ENSDARG00000076005
danio_rerio	PIEZO2	ENSDARG00000107086
danio_rerio		ENSDARG00000112723
mus_musculus	Piezo2	ENSMUSG00000041482
rattus_norvegicus	Piezo2	ENSRNOG00000038784
drosophila_melanogaster	Piezo	FBGN0264953
caenorhabditis_elegans		WBGENE00007505

Paralogs (1): PIEZO1 (ENSG00000103335)

Protein

Protein identifiers

Piezo-type mechanosensitive ion channel component 2 — Q9H5I5 (reviewed: Q9H5I5)

Alternative names: Protein FAM38B

All UniProt accessions (10): Q9H5I5, A0A2H4UKA7, A0A2R8Y3N5, A0A2R8YG64, A0A8I5KT39, E7EVM7, J3KRQ5, J3KRW1, J3QLJ9, V9GZ18

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain. Piezo channels are homotrimeric three-blade propeller-shaped structures that utilize a cap-motion and plug-and-latch mechanism to gate their ion-conducting pathways. Expressed in sensory neurons, is essential for diverse physiological processes, including respiratory control, systemic metabolism, urinary function, and proprioception. Mediates airway stretch sensing, enabling efficient respiration at birth and maintaining normal breathing in adults. It regulates brown and beige adipose tissue morphology and function, preventing systemic hypermetabolism. In the lower urinary tract, acts as a sensor in both the bladder urothelium and innervating sensory neurons being required for bladder-stretch sensing and urethral micturition reflexes, ensuring proper urinary function. Additionally, PIEZO2 serves as the principal mechanotransducer in proprioceptors, facilitating proprioception and coordinated body movements. In inner ear hair cells, PIEZO1/2 subunits may constitute part of the mechanotransducer (MET) non-selective cation channel complex where they may act as pore-forming ion-conducting component in the complex. Required for Merkel-cell mechanotransduction. Plays a major role in light-touch mechanosensation.

Subunit / interactions. Homotrimer; the homotrimer forms a propeller-shaped Piezo channel with a cation-ion conducting pore. Heterotrimeric interaction may occur between PIEZO1 and PIEZO2. Interacts with STOML3. Interacts with TMC7; the interaction inhibits PIEZO2-conducted mechanically activated currents. Interacts with TMC1; the interaction may be part of the MET complex. Interacts with MDFIC (via C-terminus); the interaction prolongs Piezo channel inactivation. Interacts with MDFI (via C-terminus); the interaction prolongs Piezo channel inactivation.

Subcellular location. Cell membrane.

Disease relevance. Arthrogryposis, distal, 5 (DA5) [MIM:108145] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA5 features include ocular abnormalities, typically ptosis, ophthalmoplegia and/or strabismus, in addition to contractures of the skeletal muscles. Some patients have pulmonary hypertension as a result of restrictive lung disease. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis, distal, 3 (DA3) [MIM:114300] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA3 features include short stature and cleft palate. The disease is caused by variants affecting the gene represented in this entry. Marden-Walker syndrome (MWKS) [MIM:248700] A syndrome characterized by a mask-like face with blepharophimosis, micrognathia, cleft or high-arched palate, low-set ears, congenital joint contractures, kyphoscoliosis, pectus excavatum or carinatum, and arachnodactyly. Additional features include decreased muscular mass, failure to thrive, renal anomalies, hypoplastic corpus callosum, cerebellar vermis hypoplasia, enlarged cisterna magna, and psychomotor retardation. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis, distal, with impaired proprioception and touch (DAIPT) [MIM:617146] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DAIPT is an autosomal recessive disease characterized by selective loss of discriminative touch perception, ataxia, difficulty walking, dysmetria, and progressive skeletal contractures. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Regulated by auxillary subunits MDFIC and MDFI. Channel activity is inhibited by TMEM120A. Phosphatidic acid and lysophosphatidic acid inhibit PIEZO2 channel activity.

Miscellaneous. Piezo comes from the Greek ‘piesi’ meaning pressure.

Similarity. Belongs to the PIEZO (TC 1.A.75) family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9H5I5-1	1	yes
Q9H5I5-2	2
Q9H5I5-3	3
Q9H5I5-4	4

RefSeq proteins (3): NP_001365112, NP_001397800, NP_071351 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027272	Piezo	Family
IPR031334	Piezo_cap_dom	Domain
IPR031805	Piezo_TM25-28	Domain
IPR056768	THU_Piezo	Domain
IPR056769	Piezo_TM1-24	Domain
IPR056770	Piezo_THU9_anchor	Domain

Pfam: PF12166, PF15917, PF23188, PF24871, PF24874

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (117 total): topological domain 39, transmembrane region 38, sequence variant 11, region of interest 8, compositionally biased region 7, sequence conflict 5, splice variant 3, glycosylation site 2, chain 1, coiled-coil region 1, modified residue 1, disulfide bond 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9VEE	ELECTRON MICROSCOPY	3.36
9VEF	ELECTRON MICROSCOPY	3.75

Predicted structure (AlphaFold)

No AlphaFold model available for Q9H5I5 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 838

Disulfide bonds (1): 1014–1192

Glycosylation sites (2): 95, 1013

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 491 (showing top): VALK_AML_WITH_FLT3_ITD, GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_MONOATOMIC_CATION_TRANSPORT, PATIL_LIVER_CANCER, GOBP_DETECTION_OF_MECHANICAL_STIMULUS, SMID_BREAST_CANCER_LUMINAL_B_UP, RIGGI_EWING_SARCOMA_PROGENITOR_DN, HNF4_DR1_Q3, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_ABIOTIC_STIMULUS, CAIRO_HEPATOBLASTOMA_UP, GOBP_DETECTION_OF_STIMULUS

GO Biological Process (9): monoatomic cation transport (GO:0006812), response to mechanical stimulus (GO:0009612), regulation of membrane potential (GO:0042391), detection of mechanical stimulus involved in sensory perception (GO:0050974), detection of mechanical stimulus (GO:0050982), cellular response to mechanical stimulus (GO:0071260), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (3): monoatomic cation channel activity (GO:0005261), mechanosensitive monoatomic ion channel activity (GO:0008381), mechanosensitive monoatomic cation channel activity (GO:0140135)

GO Cellular Component (5): plasma membrane (GO:0005886), stereocilium (GO:0032420), cuticular plate (GO:0032437), neuronal cell body membrane (GO:0032809), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion transport	2
monoatomic ion transmembrane transport	2
response to mechanical stimulus	2
monoatomic ion channel activity	2
cellular anatomical structure	2
response to external stimulus	1
response to abiotic stimulus	1
regulation of biological quality	1
sensory perception	1
detection of stimulus involved in sensory perception	1
sensory perception of mechanical stimulus	1
detection of mechanical stimulus	1
detection of external stimulus	1
detection of abiotic stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
transport	1
transmembrane transport	1
monoatomic cation transport	1
monoatomic cation transmembrane transporter activity	1
gated channel activity	1
monoatomic cation channel activity	1
mechanosensitive monoatomic ion channel activity	1
membrane	1
cell periphery	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
cortical actin cytoskeleton	1
neuronal cell body	1
cell body membrane	1

Protein interactions and networks

STRING

1777 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIEZO2	TRPV1	Q8NER1	798
PIEZO2	TRPA1	O75762	719
PIEZO2	TRPV4	Q9HBA0	692
PIEZO2	TMC2	Q8TDI7	681
PIEZO2	STOML3	Q8TAV4	671
PIEZO2	KCNK2	O95069	647
PIEZO2	LHFPL5	Q8TAF8	639
PIEZO2	KCNK4	Q9NYG8	623
PIEZO2	TMEM150C	B9EJG8	623
PIEZO2	TRPM8	Q7Z2W7	613
PIEZO2	ASIC3	Q9UHC3	608
PIEZO2	ASIC2	Q16515	601
PIEZO2	TMC1	Q8TDI8	570
PIEZO2	PIEZO1	Q92508	567
PIEZO2	SCN10A	Q9Y5Y9	540

IntAct

3 interactions, top by confidence:

A	B	Type	Score
GPC3	PXDNL	psi-mi:“MI:0914”(association)	0.350
SF3B1	FAM83G	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): PIEZO2 (Proximity Label-MS), PIEZO2 (Affinity Capture-MS), PIEZO2 (Affinity Capture-MS), STMN1 (Cross-Linking-MS (XL-MS)), PIEZO2 (Cross-Linking-MS (XL-MS)), PIEZO2 (Cross-Linking-MS (XL-MS)), PIEZO2 (Proximity Label-MS)

ESM2 similar proteins: A2CJ06, A6NGA9, A9JTM7, O54851, O70167, O70610, O95377, P16864, P18860, P25305, P28231, P28233, P28234, P28236, P29414, P33725, P36382, P51914, P51915, P57773, P69998, P69999, Q01231, Q05005, Q0VCR2, Q28GL3, Q3TT99, Q3UP23, Q5GH77, Q5M7Z0, Q5W0B7, Q6NTV1, Q6W3E5, Q6ZUK4, Q7M734, Q7RTM1, Q7TQ69, Q7ZWK8, Q80VM9, Q866T7

Diamond homologs: E2JF22, Q0KL00, Q8CD54, Q92508, Q9H5I5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PIEZO2	“form complex”	“Hair cells mechanotransduction channel”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1445 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	63
Uncertain significance	674
Likely benign	279
Benign	252

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033996	NM_001378183.1(PIEZO2):c.6614del (p.Thr2205fs)	Pathogenic
1033997	NM_001378183.1(PIEZO2):c.7807G>T (p.Glu2603Ter)	Pathogenic
1180841	NM_001378183.1(PIEZO2):c.8109T>A (p.Tyr2703Ter)	Pathogenic
1320154	NM_001378183.1(PIEZO2):c.6828-8_6829del	Pathogenic
1320155	NM_001378183.1(PIEZO2):c.704-2A>G	Pathogenic
1323449	NM_001378183.1(PIEZO2):c.4510C>T (p.Arg1504Ter)	Pathogenic
1323450	NM_001378183.1(PIEZO2):c.3585C>A (p.Cys1195Ter)	Pathogenic
1323451	NM_001378183.1(PIEZO2):c.1149dup (p.Arg384fs)	Pathogenic
1323452	NM_001378183.1(PIEZO2):c.8023C>T (p.Arg2675Ter)	Pathogenic
1323453	NM_001378183.1(PIEZO2):c.5851_5854del (p.Glu1951fs)	Pathogenic
1323455	NM_001378183.1(PIEZO2):c.433C>T (p.Gln145Ter)	Pathogenic
1331254	NM_001378183.1(PIEZO2):c.2683_2696del (p.Tyr895fs)	Pathogenic
1340728	GRCh37/hg19 18p11.21(chr18:11109971-11176380)x1	Pathogenic
137628	NM_001378183.1(PIEZO2):c.8577_8584del (p.Trp2859_Glu2862delinsTer)	Pathogenic
137629	NM_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)	Pathogenic
137631	NM_001378183.1(PIEZO2):c.8492G>T (p.Arg2831Leu)	Pathogenic
137634	NM_001378183.1(PIEZO2):c.8554T>C (p.Ser2852Pro)	Pathogenic
1447474	NM_001378183.1(PIEZO2):c.3707G>A (p.Trp1236Ter)	Pathogenic
1686064	NM_001378183.1(PIEZO2):c.5079dup (p.Asp1694fs)	Pathogenic
1686065	NM_001378183.1(PIEZO2):c.2724_2734del (p.Ser908fs)	Pathogenic
1686066	NM_001378183.1(PIEZO2):c.2372T>A (p.Ile791Lys)	Pathogenic
1706503	GRCh37/hg19 18p11.21(chr18:11087706-11346713)x1	Pathogenic
1709561	NM_001378183.1(PIEZO2):c.1549_1550insC (p.Ser517fs)	Pathogenic
1803703	NM_001378183.1(PIEZO2):c.2073C>A (p.Cys691Ter)	Pathogenic
1803704	NM_001378183.1(PIEZO2):c.1882+1G>A	Pathogenic
2041762	NM_001378183.1(PIEZO2):c.3895_3896del (p.Asn1299fs)	Pathogenic
235838	NM_001378183.1(PIEZO2):c.8547del (p.Tyr2850fs)	Pathogenic
235839	NM_001378183.1(PIEZO2):c.8514AGA[2] (p.Glu2840del)	Pathogenic
235841	NM_001378183.1(PIEZO2):c.7007C>T (p.Ser2336Leu)	Pathogenic
235842	NM_001378183.1(PIEZO2):c.7001C>T (p.Thr2334Ile)	Pathogenic

SpliceAI

10099 predictions. Top by Δscore:

Variant	Effect	Δscore
18:10677741:ACTT:A	donor_loss	1.0000
18:10677742:CTTA:C	donor_loss	1.0000
18:10677743:TTAC:T	donor_loss	1.0000
18:10677745:A:AC	donor_gain	1.0000
18:10677745:ACACT:A	donor_loss	1.0000
18:10677746:C:CA	donor_gain	1.0000
18:10677746:C:G	donor_loss	1.0000
18:10677746:CA:C	donor_gain	1.0000
18:10677746:CACT:C	donor_gain	1.0000
18:10677746:CACTG:C	donor_gain	1.0000
18:10677837:T:C	donor_gain	1.0000
18:10677873:TTT:T	acceptor_gain	1.0000
18:10677874:TT:T	acceptor_gain	1.0000
18:10677876:C:CC	acceptor_gain	1.0000
18:10680273:A:AC	donor_gain	1.0000
18:10680274:C:CC	donor_gain	1.0000
18:10682138:T:TA	donor_gain	1.0000
18:10689649:TCTTA:T	donor_loss	1.0000
18:10689650:CTTAC:C	donor_loss	1.0000
18:10689651:TTACC:T	donor_loss	1.0000
18:10689652:TACC:T	donor_loss	1.0000
18:10689653:A:AG	donor_loss	1.0000
18:10689654:C:T	donor_loss	1.0000
18:10689654:CCTT:C	donor_gain	1.0000
18:10691223:AC:A	donor_gain	1.0000
18:10691224:CC:C	donor_gain	1.0000
18:10696165:T:TA	donor_gain	1.0000
18:10697746:A:AC	donor_gain	1.0000
18:10697747:C:CC	donor_gain	1.0000
18:10697747:CTT:C	donor_gain	1.0000

AlphaMissense

19009 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:10671550:A:G	W2746R	1.000
18:10671550:A:T	W2746R	1.000
18:10671555:A:C	I2744S	1.000
18:10671555:A:G	I2744T	1.000
18:10671555:A:T	I2744N	1.000
18:10671567:G:T	P2740Q	1.000
18:10671573:C:G	R2738P	1.000
18:10671574:G:T	R2738S	1.000
18:10671577:A:C	Y2737D	1.000
18:10671579:A:G	L2736P	1.000
18:10671581:G:C	F2735L	1.000
18:10671581:G:T	F2735L	1.000
18:10671582:A:G	F2735S	1.000
18:10671583:A:G	F2735L	1.000
18:10671585:A:T	I2734K	1.000
18:10671588:A:G	L2733S	1.000
18:10671600:A:G	L2729P	1.000
18:10671608:T:A	E2726D	1.000
18:10671608:T:G	E2726D	1.000
18:10671612:A:G	L2725P	1.000
18:10671633:C:G	R2718P	1.000
18:10671641:A:C	F2715L	1.000
18:10671641:A:T	F2715L	1.000
18:10671643:A:G	F2715L	1.000
18:10671653:G:C	C2711W	1.000
18:10671654:C:T	C2711Y	1.000
18:10671655:A:G	C2711R	1.000
18:10671657:A:G	L2710S	1.000
18:10671684:A:G	L2701P	1.000
18:10671692:A:C	F2698L	1.000

dbSNP variants (sampled 300 via entrez): RS1000012676 (18:11110443 C>T), RS1000014780 (18:10722627 A>C), RS1000023462 (18:10899408 C>T), RS1000026859 (18:10808488 T>C), RS1000027424 (18:10846134 A>C), RS1000028068 (18:11017056 T>C), RS1000034798 (18:11010471 C>T), RS1000035321 (18:10977760 A>G,T), RS1000046748 (18:10686423 A>C), RS1000056767 (18:11013197 T>C), RS1000058555 (18:10689871 C>A,T), RS1000058744 (18:10705383 T>A,C,G), RS1000063117 (18:10728360 C>T), RS1000067072 (18:10936872 G>A), RS1000068955 (18:10972998 C>A,G)

Disease associations

OMIM: gene MIM:613629 | disease phenotypes: MIM:248700, MIM:617146, MIM:114300, MIM:108145, MIM:617468, MIM:208150, MIM:108120, MIM:181500, MIM:613751

GenCC curated gene-disease

Disease	Classification	Inheritance
Gordon syndrome	Definitive	Autosomal dominant
arthrogryposis, distal, with impaired proprioception and touch	Definitive	Autosomal recessive
arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome	Strong	Autosomal dominant
Marden-Walker syndrome	Moderate	Autosomal dominant
connective tissue disorder	Moderate	Autosomal recessive

Mondo (16): Marden-Walker syndrome (MONDO:0009564), arthrogryposis, distal, with impaired proprioception and touch (MONDO:0014941), Gordon syndrome (MONDO:0007252), arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (MONDO:0007158), cerebral palsy (MONDO:0006497), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), exocrine pancreatic insufficiency (MONDO:0001684), scoliosis (MONDO:0005392), distal arthrogryposis (MONDO:0019942), schizophrenia (MONDO:0005090), cleft palate (MONDO:0016064), heterotaxy, visceral, 4, autosomal (MONDO:0013403), congenital contractures (MONDO:0022823), myopathy (MONDO:0005336)

Orphanet (9): Marden-Walker syndrome (Orphanet:2461), Gordon syndrome (Orphanet:376), Arthrogryposis-oculomotor limitation-electroretinal anomalies syndrome (Orphanet:1154), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), Distal arthrogryposis (Orphanet:97120), Cleft palate (Orphanet:2014), Visceral heterotaxy (Orphanet:450), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

175 total (30 of 175 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000036	Abnormal penis morphology
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000072	Hydroureter
HP:0000077	Abnormality of the kidney
HP:0000079	Abnormality of the urinary system
HP:0000089	Renal hypoplasia
HP:0000104	Renal agenesis
HP:0000110	Renal dysplasia
HP:0000126	Hydronephrosis
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000260	Wide anterior fontanel
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000298	Mask-like facies
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001210_1	Non-small cell lung cancer	1.000000e-06
GCST001786_1	Dental caries	9.000000e-06
GCST001821_1	Metabolite levels (5-HIAA/ MHPG Ratio)	8.000000e-06
GCST001850_32	Major depressive disorder	4.000000e-06
GCST001850_47	Major depressive disorder	3.000000e-06
GCST001859_4	Thiazide-induced adverse metabolic effects in hypertensive patients	3.000000e-07
GCST002337_18	Amyotrophic lateral sclerosis (sporadic)	9.000000e-07
GCST003026_5	Yu-Zhi constitution type in type 2 diabetes	1.000000e-06
GCST003263_26	Post bronchodilator FEV1 in COPD	5.000000e-06
GCST003263_96	Post bronchodilator FEV1 in COPD	4.000000e-06
GCST006630_79	Diastolic blood pressure	5.000000e-17

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005132	5-HIAA measurement
EFO:0005133	MHPG measurement
EFO:0004530	triglyceride measurement
EFO:0007638	Yu-Zhi constitution type
EFO:0004314	forced expiratory volume
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003240	Connective Tissue Diseases	C17.300
D010188	Exocrine Pancreatic Insufficiency	C06.689.276
D012600	Scoliosis	C05.116.900.800.875
C537288	Gordon syndrome (supp.)
C535910	Marden-Walker syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Piezo channels

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
GsMTx-4	Inhibition	5.3	pIC50

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	8
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, affects expression	5
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases methylation	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
Acetaminophen	increases expression, decreases expression	2
Air Pollutants	increases abundance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
FR900359	increases phosphorylation	1
sotorasib	affects cotreatment, increases expression	1
propionaldehyde	decreases expression	1
trichostatin A	increases expression	1
hydroxyhydroquinone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
diallyl trisulfide	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	decreases methylation	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Panobinostat	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F1TH	HyCyte SH-SY5Y KO-hPIEZO2	Cancer cell line	Female

Clinical trials (associated diseases)

383 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment