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24

Lab Times

1-2015

Journal Club

Forty degrees in the shade and you are soaking wet. Sweating cools our bodies but members of a Pakistani fam-

ily cannot rely on this bodily function, they suffer from anhydrosis. What causes this disorder? Joakim Klar in the

group of Niklas Dahl found a tiny mutation with big consequences.

Working Up

a Sweat

Human genetics in Uppsala, Sweden

I

magine the sun is shining outside. With-

out you giving it much thought, your

body is able to activate its in-built cool-

ing system – aka sweat glands – and bring

your body temperature to a more pleasant

level. Sweating is a bodily function, ignored

at best and often cursed if in excess, but

without it, you may be in serious trouble.

Medically, this is known as anhydrosis and

for a particular family in Pakistan, it has be-

come a daily plight for five of its members.

The affected family members have had

to develop ingenious ways to avoid hot

temperatures, including staying in a cellar

during the day and putting wet sheets over

their body to avoid increased heart rate and

heatstroke.

“Sweating is the number one

physical property we have to cool

down our body. What we can see

in our patients is that they com-

pletely lack sweating and they

cannot cool down when the tem-

perature goes up,” says Joakim

Klar from Uppsala University

in Sweden and lead author in a

study published recently, looking

in-depth at what may be causing

the condition for this family (

J

Clin Invest,

124, 4773-80).

When sweating is impossible

It’s known that use of certain

drugs or skin conditions can affect

or block sweat glands, with the re-

sult that sweating is impossible. In this case,

however, all family members have morpho-

logically normal sweat glands. Intrigued by

this conundrum, the team, led by geneti-

cist Niklas Dahl, decided to explore further.

Dahl’s group often studies rare genetic dis-

orders, with the aim of identifying the mu-

tated genes behind them and developing

potential treatments.

After a little digging, a whole-genome

search revealed a single-amino acid muta-

tion (glycine to serine) in amino acid 7492

in a gene called

ITPR2

. This gene encodes

for a type of inositol 1,4,5-triphosphate re-

ceptor, well-known for its involvement in

regulating calcium release from the endo-

plasmic reticulum into the cell cytosol.

What may at first glance seem like a mu-

tation with mild consequences, has in fact a

very strong impact on receptor function. It

turns out that the “G-to-S” mutation is lo-

cated in the pore domain and completely

obstructs the receptor’s ability to dispense

calcium. The mutated version of the recep-

tor is still able to form its transmenbrane

structure with a normal calcium storage

area but this mineral cannot be evacuated

via the excretory duct to trigger sweat pro-

duction. Not surprisingly, when the team

conducted

in vitro

studies using mutated

versions of this receptor, they could not ac-

tivate the cell’s normal response involving

intracellular calcium oscillations.

As the release of calcium from the en-

doplasmic reticulum is essential to regu-

late many cellular mechanisms throughout

the body, the next question soon became,

why is this mutation only affecting sweat

glands. The answer involves this receptor

– commonly referred to as a type 2 recep-

tor – and two others, forming a family with

identical functions ubiquitously distributed

in the body. This means most cells will have

at least one fully working copy to compen-

sate for the lack of active type 2 receptors.

An evolutionarily lucky deletion

Rather incredibly, this includes the cal-

cium storage section of the sweat glands

themselves, where type 3 receptors are

abundant. However, evolution “deleted”

these receptors from the release channels

in these glands, and only type 2

receptors seem to be present. As

a consequence, all family mem-

bers affected are normal and

healthy, with the only exception

of not being able to sweat. “You

have these receptors in other

cells, and they’re important for

many functions in the body”,

says Klar, “but fortunately for

this family, the only thing that is

affected is the sweat gland, oth-

erwise they would have prob-

lems in many cells.”

Since their discovery in the

late 1980s, studying these re-

ceptors has attracted much at-

tention and their activity has

been associated with many different cellu-

lar and physiological processes, from ferti-

lisation to hair loss.

This includes long time researcher in

this field, Katsuhiko Mikoshiba, who has

successfully developed knockout mice lack-

ing each individual inositol receptor. As an

example, his team has shown that lack of

type 3 receptors affects taste perception for

By the sweat on their brows, Niklas Dahl (centre), Joakim Dahl (2

nd

from

left) and the rest of the Uppsala team pinpointed the mutation that

leads to anhydrosis in a Pakistani family.

Photo: Dahl lab

Photo: Fotolia/eunikas