Yes mutations have been linked

Yes, mutations have been linked to two main types of disorder in humans. Several autosomal dominant mutations, some of which have been characterized and lead to increased PIEZO1 signaling, are associated with dehydrated hereditary stomatocytosis (DHS). DHS is characterized by osmotically-driven dehydration of red blood PPDA that can lead to haemolytic anaemia. Therefore, deletion in mice leads to overhydrated red blood cells, whereas ‘gain of function’ mutations associated with DHS in humans lead to dehydrated red blood cells, highlighting the crucial role of this channel in volume homeostasis in red blood cells. Other mutations resulting in attenuated or disrupted PIEZO1 function have been linked to autosomal recessive generalized lymphatic dysplasia, a congenital disease that causes persistent lymphoedema, revealing the involvement of PIEZO1 in the development of lymphatic structure. It should be noted that Piezo1 is a widely-expressed ion channel and the full extent to which it regulates development and physiology is yet to be elucidated. Autosomal dominant mutations thought to cause a ‘gain of function’ effect have been linked to different forms of distal arthrogryposis and to Marden-Walker syndrome. These conditions are multi-symptomatic human disorders presenting overlapping phenotypic characteristics, including short stature, curved fingers with straight thumbs and contractures of hands and feet. The broad spectrum of clinical defects associated with these diseases suggests that PIEZO2 is involved in the development and function of various structures in the body. Furthermore, several cases of recessive mutations leading to truncated or malfunctioning PIEZO2 channels have been reported. Patients bearing these mutations display a progressive phenotype that is mostly distinct from that resulting from dominant mutations, although there is a partial overlap, with both types of mutation giving rise to short stature and contractures. In addition to scoliosis, myopathy and progressive respiratory failure, disruption of PIEZO2 function leads to impairments in proprioception and discriminative touch perception, in agreement with the critical role of Piezo2 in light-touch sensing and proprioception in mice.
Introduction Red blood cells (RBCs) are major blood constituents serving primarily to transport oxygen and carbon dioxide. Nonnucleated mammalian RBCs in particular are much simpler than most other eukaryotic cells because they consist essentially of a dense hemoglobin solution enclosed by a smooth and laterally incompressible membrane. In the course of blood circulation, RBCs are exposed to various external forces that change their shape. In capillaries, they resemble a parachute, whereas in the absence of constraints or other external forces, they resemble an axially compressed disc (1). An RBC can change its shape because of the flexibility of its membrane and because of its small (≈0.6) reduced volume (i.e., volume divided by the volume of a sphere with the same surface area) (2). Water moves through the membrane of an RBC sufficiently fast for its volume to be established as the result of the osmotic equilibrium between its internal and external solutions (3). Hemoglobin cannot cross the RBC membrane so that the cell has a tendency to swell. However, because of the control of its cytoplasmic content of potassium, sodium, and chloride ions, its volume remains steady (4). RBC anions exchange much faster than RBC cations and can be considered to be in thermodynamic equilibrium with their outer counterparts. The content of RBC potassium and sodium is established by a pump-leak mechanism (5) based on a sodium-potassium pump that uses cell ATP to expel sodium and take in potassium, together with several channels through which potassium and sodium ions leak through the membrane in the direction of their concentration gradients (6). Piezo channels (Piezo1 and Piezo2) are large, transmembrane proteins, whose subunits have more than 2500 amino acids. They are involved in processes like touch and sound reception acting to transform mechanical stimulation into a transmembrane flow of cations (7, 8). RBC membranes contain only Piezo1, which plays the role in the establishment of the cell volume, as indicated by the fact that its mutants cause the hereditary disease, xerocytosis (dehydrated stomatocytosis) (9). Cryoelectron microscopy structural studies have shown that the Piezo1 channel operates in the form of a homotrimer (10, 11, 12, 13). The mode of action of Piezo1 in RBCs was revealed by Cahalan et al. (14) who showed, by comparing the behavior of normal mouse RBCs and RBCs of the corresponding Piezo1 knockout mice, that openings of Piezo1 channels lead to a transient increase of cytoplasmic Ca2+ concentration thus triggering increased K+ efflux by activating Ca2+ activated K+ (Gárdos) channels (15).