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Touch Perception Linked to Ion Channel Using Patient Exome Data

NEW YORK (GenomeWeb) – While attempting to diagnose individuals with an unusual neuromuscular and skeletal condition, researchers from the US and Canada have detected a role for the ion channel PIEZO2 in some aspects of normal touch or force-sensing functions.

Using exome sequencing on two individuals with similar, difficult-to-diagnose conditions, the team identified recessive, compound heterozygous mutations in the PIEZO2 gene that appeared to contribute to symptoms such as vibratory touch perception, motor impairments, progressive scoliosis, and other skeletal deformations.

As they reported in the New England Journal of Medicine yesterday, the researchers subsequently verified the role of the gene and its protein product in a specific set of mechanosensory functions through follow-up cell line, expression, and sensory testing experiments.

"Our results show that PIEZO2 is a determinant of mechanosensation in humans," senior author Carsten Bönnemann, a researcher with the National Institute of Neurological Disorders and Stroke, and his colleagues wrote.

Prior anatomical studies have identified different types of neurons involved in sense of touch but the complete circuitry of mechanosensation and its interactions with movement, posture, and pain perception are yet to be resolved. And though PIEZO2 has been linked to touch response, proprioception, and some somatosensory neuron functions in mice or in vitro systems, the researchers noted that "[a]lmost nothing is known about the role of PIEZO2 in humans."

To explore molecular factors involved in touch perception, the team focused on two girls with similar neuromuscular and mechanosensory conditions that could not be diagnosed: a 19-year-old girl from Bangladesh and a 10-year-old girl with European and Japanese ancestry. Both had similar touch perception, scoliosis, and gait problems, without deficits in cognition.

After capturing protein-coding portions of each patient's genome with a Roche NimbleGen SeqCap EZ exome kit, the researchers sequenced the exomes using Illumina HiSeq 2500 instruments. They then analyzed the sequences, sifting out variants that were present in databases such as dbSNP; the National Heart, Lung, and Blood Institute's Exome Variant Server; and the Exome Aggregation Consortium set.

In both patients, they tracked down nonsense mutations in one copy of the PIEZO2 gene and a premature stop mutation in the other copy — mutations validated by Sanger sequencing.

To begin investigating the consequences of these alterations, the team transfected a human embryonic kidney cell line that does not normally express PIEZO2 with mouse versions of the gene containing the variants found in each patient. The variants coincided with non-functional protein products in the cell line — consistent with the lower-than-usual levels of PIEZO2 in skin biopsy samples from each patient.

But while both individuals were relatively oblivious to vibrations or light touches to the palm or fingertip — skin that is usually particularly perceptive to touch — the researchers noted that they were still sensitive to other stimuli such as temperature, pinpricks, pokes, or brush strokes on forearm hair. Based on these observations, they speculated that there are likely multiple mechanosensation systems that help us orient our bodies and respond to different types of stimuli depending on skin sites.

"The findings of this study and those of others show the way in which distinct and independent peripheral lines of input combine to provide the rich sensory experience of human touch and the perception of our bodies in space," the authors wrote.