The PIEZO2 gene encodes a large protein containing 31 transmembrane domains. This protein is believed to function as part of the principal mechano-transduction cation channel and is therefore essential for the rapid adaptation of mechanically-activated currents in somatosensory neurons. It plays a key role in the detection of mechanical stimulus and is also involved in the response to said mechanical stimulus. It is hence essential for perceiving the sensations of touch and proprioception.
Mutations in the gene are associated with the 3 overlapping autosomal dominant conditions of Marden-Walker Syndrome (MWKS), Distal Arthrogryposis Type 3 (DA3) and Distal Arthrogryposis Type 5 (DA5). PIEZO2 gene mutations have also been implicated in the autosomal recessive disorder of Distal Arthrogryposis with Impaired Proprioception and Touch (DAIPT).
The PIEZO2 gene is located on the short arm of chromosome 18. It spans a length of 482 kb of DNA and its coding sequence is spread across 55 exons. The protein product encoded by this gene has a molecular mass of 318 kDa and consists of 2752 amino acids. Several additional isoforms of the PIEZO2 protein exist due to alternatively spliced transcript variants. The gene is found to be overexpressed in the brain, spinal cord, pancreas, liver and lung. Heterozygous mutations in the PIEZO2 gene, including missense variants and deletions, have been linked to the disorders of MWKS, DA3 and DA5. So far only one mutation (R2686C) has been identified in MWKS. Homozygous and compound heterozygous mutations in the gene associated with Distal Arthrogryposis, with Impaired Proprioception and Touch (DAIPT) mainly include nonsense variants and deletions that cause frameshift and premature truncation, often resulting in a non-functioning PIEZO2 protein.
Monies et al. (2017) reported the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 12-year-old female from a consanguineous family, suffered from severe lower limb weakness, progressive scoliosis and suspected SMA but did not have arthrogryposis. She also reported a family history of this phenotype. Using whole exome sequencing, a homozygous mutation (c.273_279del, p.A91fs) was identified in exon 3 of the patient’s PIEZO2 gene, associated with DAIPT. Given the atypical presentation of the patient, this case helped in the phenotypic expansion of the disorder.
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