A Crucial Step in Unravelling Molecular Mechanism behind CMT--Defects in the YAR

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A Crucial Step in Unravelling Molecular Mechanism behind CMT--Defects

in the YARS Gene

Antwerp, Belgium - February 2006:

Researchers of the Flanders Interuniversity Institute for

Biotechnology (VIB) at the University of Antwerp have again taken a

crucial step in unravelling the molecular mechanism behind the

Charcot-Marie-Tooth (CMT) disorder, which is a disease of the nervous

system that leads to muscular atrophy. Dr. Albena Jordanova, a

Bulgarian guest researcher at the University of Antwerp, discovered

that CMT patients have a specific mutation in an enzyme (YARS) that

plays an important role in protein synthesis in all forms of life.

This suggests that YARS is involved in disorders of the peripheral

nervous system, which in turn may open the way to methods for

preventing or treating CMT.

The focus of the research team led by Prof. Timmerman (VIB

Molecular Genetics Department, University of Antwerp) is identifying

and studying genes that are involved in CMT and other hereditary

disorders of the peripheral nervous system. Research recently

conducted by Bulgarian guest researcher Dr. Albena Jordanova has now

revealed a new aspect of the molecular process behind CMT.

Defects in the YARS gene

Dr. Jordanova studied two families, one in Bulgaria and one in

America, in which CMT has been present for several generations. She

studied archives and interviewed affected persons and other, healthy

family members. In this manner, she was able to reconstruct two

enormous family trees that showed how the disease was passed on by

inheritance during the past 200 years. In genetic material from the

Bulgarian and American CMT families, she localized the disorder to

chromosome 1. After a long investigation of this chromosome, she

discovered that the affected family members hadsystematic defects in

the gene that codes for the YARS enzyme (tyrosyl-tRNA synthetase).

Two mutations of the YARS gene were found in the Bulgarian and

American families. At the same time, it was found that the YARS

protein of a Belgian CMT family was missing several amino acids.

Those were important findings, because YARS is an important factor in

the life of people, animals and plants everywhere in the world. It

contributes to the production of essential proteins, and it was

already present in the earliest forms of life on our planet. The

discovery that deviant forms of YARS were present in CMT patients

thus suggested that they suffered from some sort of shortcoming in a

fundamental bodily process.

In the next stage of her research, Dr. Jordanova investigated the

consequences of this YARS mutation in living cells. Mutant YARS was

introduced into yeast cells, and the growth of the yeast cultures was

monitored. That revealed that the mutated YARS retarded the growth of

the yeast cells. After this, she focused specifically on the activity

of the YARS enzyme. That study showed that YARS has a reduced level

of activity in CMT patients. She also discovered that YARS is

localized in nerve tips, and that the amount of YARS present there is

reduced if the cells have mutated with mutant YARS. As human

peripheral nerves can be up to 1 meter long (such as the nerves that

run from the spinal column to the feet), that led to the conjecture

that YARS might be involved in transmitting signals from the nerve

tips to the muscles. That formed an important hypothesis in

unravelling the CMT puzzle, in which something goes wrong with the

signals transmitted by the nerves to control muscle activity.

The search continues

Three years of scientific research have yielded an important clue in

the battle against a frequently occurring hereditary disorder that

can have drastic consequences. Reconstruction of the Bulgarian family

tree – which required visiting family members in extremely remote

mountain villages – was a monumental effort, and the subsequent

studies were also very labor-intensive, but they have yielded truly

worthwhile results. The next task is to understand the exact role of

YARS, which can be helpful in establishing a diagnosis and

determining the risk for a child with CMT. Particularly in Bulgaria,

where CMT is the most commonly occurring neuromuscular disease, that

can make a major difference in national health care.

Dr. Jordanova, who was recently awarded the `Women in Science' prize

in Bulgaria, is returning to the Medical University of Sofia after

completing her research. There she will resume her position of

Assistant Professor at the Laboratory of Molecular Pathology.

However, she said she hoped to return to Antwerp some time to

continue her research with what she called `the best people in the

world in molecular genetics'.

Relevant scientific publication:

" Disrupted function and axonal distribution of mutant tyrosyl-tRNA

synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy "

in Nature Genetics 2006 (Jordanova et. al. – on line 22 January 2006)

The research was performed in cooperation with research groups

associated with the universities of Antwerp, Ghent and Leuven. Prof.

Johan Thevelein and Prof. Van Dijck (VIB Department of

Molecular Microbiology, C.U. Leuven) assisted in the yeast study.

Prof. Jan Gettemans and Dr Kris Meerschaert (VIB Department of

Medical Protein Research, U. Ghent) were involved in measuring the

enzyme activity of YARS. The nerve cell research was supported by

Prof. Wim Robberecht and Prof. Ludo Van den Bosch of the C.U. Leuven.

The microscope studies were performed in the laboratory of Prof. Jean-

Pierre Timmermans (University of Antwerp).