Scientists unravel the mystery of a rare sweating disorder

October 20, 2014

An international research team discovered that mutation of a single gene blocks sweat production, a dangerous condition due to an increased risk of hyperthermia, also known as heatstroke. The gene, ITPR2, controls a basic cellular process in sweat glands, promoting the release of calcium necessary for normal sweat production, and its loss results in impaired sweat secretion.

The study, published on October 20, in the Journal of Clinical Investigation, was led by Katsuhiko Mikoshiba, a molecular cell biologist from the RIKEN Brain Science Institute in Japan and Niklas Dahl, a genetics expert at Uppsala University in Sweden.

Dr. Dahl's group studies rare single-gene diseases, also known as Mendelian disorders, with the goal of identifying causative genes to develop diagnostic or treatment tools. Working with collaborators in Pakistan, they identified a family with several children who could not sweat, a rare condition called anhidrosis.

Sweating serves to regulate body temperature and keeps animals from overheating. Although excessive sweating is an embarrassing problem, an inability to sweat is potentially lethal, as it impairs the body's ability to regulate temperature and increases susceptibility to heatstroke.

Anhidrosis can have several causes, including genetic, in which case the sweat glands are either deformed or missing. In contrast, the sweat glands of the individuals examined in this study appeared visually normal and no other physical problems were reported.

Analysis of the patients' genomes revealed a mutation in a gene called ITPR2, which encodes IP3 receptor type 2 (IP3R2), a protein that forms a channel in the membrane of the endoplasmic reticulum, an organelle within cells that stores an ion called calcium. Opening of the IP3R channel releases calcium, triggering essential cell behaviors such as movement, shape changes, or secretion.

In order to understand how the mutation caused a lack of sweat production, Dr. Dahl sought collaboration with Dr. Mikoshiba, who discovered the IP3 receptor. "This is the first report of IP3 receptor type 2 mutation in human disease," said Dr. Mikoshiba. "The surprise was that a point mutation, not a large deletion was enough to cause the human disorder."

Dr. Mikoshiba's group examined the function of the mutated IP3R2 protein in cultured cells and found that a single nucleotide change in the DNA code resulted in a change in protein structure impeding the ability of the channel to release calcium. The team then examined sweat production in mice with a genetic loss of the IP3R2 protein and found that they had reduced sweating.

Calcium release is a potent signal within cells and some animals have several IP3 receptor types to compensate for each other if one is not functioning properly. The researchers found that human sweat glands mainly have IP3R2. However, in mouse, sweat glands also have R1 that may partially make up for the lack of R2, explaining why the mutant mice were still able to produce some sweat.

"Although anhidrosis is quite a rare condition, the 'opposite' phenotype, excess sweating or hyperhidrosis, is a common problem affecting 2% of the population" said Dr. Dahl. "Such symptoms may be alleviated by a drug that inhibits IP3R2. However," he cautions, "IP3R2 is expressed in many tissues, and compounds must first be carefully evaluated in experimental models." Efforts to develop drugs to regulate the IP3R are currently underway.
-end-


RIKEN

Related Protein Articles from Brightsurf:

The protein dress of a neuron
New method marks proteins and reveals the receptors in which neurons are dressed

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.

Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.

A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.

A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.

Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.

A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.

A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.

Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.

Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.

Read More: Protein News and Protein Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.