GeneBe

PIEZO2

protein-coding

piezo type mechanosensitive ion channel component 2, the group of Armadillo like helical domain containing|MicroRNA protein coding host genes

Gene summary

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. [provided by RefSeq, Feb 2014]

Previous symbols:
  • FAM38B2
  • C18orf30
  • C18orf58
  • FAM38B

MANE transcript

NM_001378183.1

Inheritance

AR, AD

ClinVar variants

P:154U:722B:294

Top phenotype

Arthrogryposis, distal, type 3; Arthrogryposis, distal, type 5; Marden-Walker syndrome; Arthrogryposis, distal, with impaired proprioception and touch

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr18:10,666,483-11,149,569

External References & Databases

Ensembl (ENSG00000154864)NCBI Gene (63895)OMIM (613629)HGNC:26270GenCCUniProt (Q9H5I5)AlphaFoldClinVar (PIEZO2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~483.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

arthrogryposis, distal, with impaired proprioception and touchSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014941

Submitter: PanelApp Australia

arthrogryposis, distal, with impaired proprioception and touchSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014941

Submitter: Labcorp Genetics (formerly Invitae)

Gordon syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007252

Submitter: Orphanet

arthrogryposis- oculomotor limitation-electroretinal anomalies syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007158

Submitter: Orphanet

Marden-Walker syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009564

Submitter: Orphanet

Gordon syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007252

Submitter: G2P

arthrogryposis, distal, with impaired proprioception and touchDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014941

Submitter: Illumina

Gordon syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007252

Submitter: Labcorp Genetics (formerly Invitae)

arthrogryposis, distal, with impaired proprioception and touchDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014941

Submitter: G2P

Marden-Walker syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009564

Submitter: Genomics England PanelApp

arthrogryposis- oculomotor limitation-electroretinal anomalies syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007158

Submitter: PanelApp Australia

connective tissue disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0003900

Submitter: Genomics England PanelApp

Marden-Walker syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009564

Submitter: Ambry Genetics

arthrogryposis, distal, with impaired proprioception and touchMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014941

Submitter: Ambry Genetics

arthrogryposis- oculomotor limitation-electroretinal anomalies syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007158

Submitter: Ambry Genetics

Gordon syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007252

Submitter: Ambry Genetics

arthrogryposis, distal, with impaired proprioception and touchDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014941

Submitter: Illumina

The PIEZO2 gene is located on chromosome 18 at p11.22-p11.21 and encodes the piezo type mechanosensitive ion channel component 2 protein, a rapidly adapting mechanically-activated cation channel that is required for touch sensation and proprioception (25471886: Ranade et al. 2014; 26551544: Woo et al. 2014). PIEZO2 was first reported in association with autosomal recessive distal arthrogryposis with impaired proprioception and touch in 2016 (27653382: Chesler et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants reported in seven cases from four publications (27653382: Chesler et al. 2016; 27843126: Delle Vedove et al. 2016; 27607563: Mahmud et al. 2017; 30941898: Yamaguchi et al. 2019). One variant was a missense with experimental evidence of a loss-of-function effect; the remainder were predicted null variants. No segregation evidence was scored, but variants in this gene co-segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Biallelic loss of function is implicated as the mechanism of disease. This gene-disease relationship is supported by tissue-specific expression in mechanoreceptors that sense mechanical stimuli relevant to touch sensation and in all types of proprioceptive peripheral endings (20813920: Coste et al. 2010; 25471886: Ranade et al. 2014; 26551544: Woo et al. 2014). Conditional knockout of PIEZO2 in sensory neurons and epidermal Merkel cells causes impaired touch sensation, and conditional knockout in proprioceptors resulted in impaired proprioception and difficulty walking (25471886: Ranade et al. 2014; 26551544: Woo et al. 2014). In summary, PIEZO2 is definitively associated with autosomal recessive distal arthrogryposis with impaired proprioception and touch. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Gordon syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007252

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Arthrogryposis, distal, type 3; Arthrogryposis, distal, type 5; Marden-Walker syndrome; Arthrogryposis, distal, with impaired proprioception and touchAD/AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23487782; 24726473; 27607563; 27653382Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIEZO2 variants in ClinVar

32 Conditions Cataloged
not providedTotal: 783
Inborn genetic diseasesTotal: 435
not specifiedTotal: 165
Arthrogryposis, distal, with impaired proprioception and touchTotal: 117
PIEZO2-related disorderTotal: 89
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndromeTotal: 52
Gordon syndromeTotal: 50
Marden-Walker syndromeTotal: 45

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378183.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
7
clinvar
196
clinvar
10
clinvar
 213
missense
9
clinvar
19
clinvar
707
clinvar
78
clinvar
9
clinvar
 822
nonsense
20
clinvar
30
clinvar
5
clinvar
 55
start loss
0
frameshift
20
clinvar
28
clinvar
2
clinvar
1
clinvar
 51
splice donor/acceptor (+/-2bp)
8
clinvar
20
clinvar
1
clinvar
 29
Total5797722275191170

Highest pathogenic variant AF is 0.00003057937

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001378183.1RefSeqNP_001365112.156MANE Select
ENST00000674853.1EnsemblENSP00000501957.156MANE Select
NM_001410871.1RefSeqNP_001397800.154Standard
NM_022068.4RefSeqNP_071351.252Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
piezo2bDanio rerio

Structure: thigmotropism

Quality: decreased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • cation transport
  • response to mechanical stimulus
  • regulation of membrane potential
  • detection of mechanical stimulus involved in sensory perception
  • detection of mechanical stimulus

Molecular Function

  • cation channel activity
  • mechanosensitive ion channel activity

Cellular Component

  • plasma membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000503781
Coding exons
52
Length
482108
Individuals with no LoFs
125714
Homozygous LoFs
0
Heterozygous LoFs
34
Defined
125748
p
0.000135
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.4410811.45e+30.7450.000080418140
Missense (PolyPhen)288501.680.574076409
Synonymous2.314815500.8750.00003305044
Loss of Function7.85401400.2850.000007491749

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000220.00021rare
South Asian00.0absent
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of a mechanosensitive channel required for rapidly adapting mechanically activated (MA) currents. Required for Merkel-cell mechanotransduction. Plays a major role in light- touch mechanosensation. {ECO:0000250|UniProtKB:Q8CD54}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:23487782, ECO:0000269|PubMed:24726473}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:24726473}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:24726473}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:27607563, ECO:0000269|PubMed:27653382}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.106

Essentials

Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.114

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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