PIEZO2 – Arthrogryposis-Oculomotor Limitation-Electroretinal Anomalies Syndrome

PIEZO2 encodes a mechanically activated ion channel required for mechanotransduction in proprioceptors. Heterozygous gain-of-function variants in PIEZO2 underlie a clinically distinct subtype of distal arthrogryposis, arthrogryposis-oculomotor limitation-electroretinal anomalies syndrome (DA5), characterized by congenital contractures of the distal joints, ptosis, ophthalmoplegia, triangular facies, short stature and restrictive pulmonary function ([PMID:23487782]). Initial linkage of PIEZO2 to DA5 was demonstrated by electrophysiological assays showing that E2727del and I802F mutations prolong channel open time and accelerate recovery from inactivation, leading to increased mechanosensitive currents ([PMID:23487782]).

Subsequent case reports describe a three-generation Canadian family carrying c.8068A>C (p.Ser2690Arg) segregating with DA5 features in all affected members ([PMID:30938034]) and a four-generation Italian pedigree harboring c.8181_8183delAGA (p.Glu2727del) in five affected relatives including the proband, mother, grandfather and great-grandmother ([PMID:35906671]). These reports expand the allelic and phenotypic spectrum of PIEZO2-related DA5.

A landmark multi-cohort study sequenced PIEZO2 in 29 DA5 families, 12 Gordon syndrome (GS) families and two Marden-Walker syndrome (MWS) cases, identifying pathogenic variants in 24/29 (83%) DA5, 10/12 (83%) GS and 1/2 MWS families. The recurrent c.8057G>A (p.Ser2686Asn) allele was present in nine unrelated families and significantly associated with cleft palate ([PMID:24726473]). In total, over 29 distinct variants—predominantly missense—have been reported in >60 families, demonstrating autosomal dominant inheritance with segregation in five additional affected relatives.

Functional studies consistently support a gain-of-function mechanism: electrophysiological characterization of p.Ile802Phe and p.Glu2727del shows altered inactivation kinetics and increased channel activity, correlating with the DA5 phenotype ([PMID:23487782]). Overexpression assays confirm that mutated PIEZO2 channels do not exhibit constitutive toxicity, implicating dysregulated mechanotransduction rather than cell death in pathogenesis.

By contrast, biallelic loss-of-function PIEZO2 variants cause a distinct progressive arthrogryposis syndrome with impaired proprioception and touch, demonstrating that dominant gain-of-function and recessive loss-of-function mutations yield divergent clinical entities ([PMID:27607563]). No studies have refuted the association of PIEZO2 gain-of-function variants with DA5.

Collectively, robust genetic and experimental data unequivocally establish PIEZO2 as a definitive DA5 gene. Identification of a pathogenic PIEZO2 variant informs precise diagnosis, enables tailored management of contractures and respiratory compromise, and guides genetic counseling.

Key Take-home: Heterozygous gain-of-function PIEZO2 variants cause a clinically recognizable autosomal dominant distal arthrogryposis (DA5), with strong diagnostic and prognostic utility.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis PMID:23487782
• American journal of medical genetics. Part A • 2019 • Distal arthrogryposis type 5 and PIEZO2 novel variant in a Canadian family. PMID:30938034
• Italian journal of pediatrics • 2022 • Distal Arthrogryposis type 5 in an Italian family due to an autosomal dominant gain-of-function mutation of the PIEZO2 gene. PMID:35906671
• American journal of human genetics • 2014 • Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. PMID:24726473
• Clinical genetics • 2017 • Loss of the proprioception and touch sensation channel PIEZO2 in siblings with a progressive form of contractures. PMID:27607563

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