Supplying the missing building block in brain atrophy

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Supplying the missing building block in brain atrophy

By Gilah Kahn-Hoffman

November 15, 2010

Having identified the protein building block missing in patients with brain

atrophy, Israeli researchers can now conceive of a way to replace it.

The figures depict the progressive wasting away of brain tissue, beginning with

normal appearance at eight months (left), moving to progressive loss of brain

tissue by 18 months (middle) and then at three years (right).

An Israeli scientist has identified a genetic mutation that leads to progressive

brain atrophy. His research team has detected a defect in the 21st amino acid

that results in a progressive disease of severe mental retardation and epilepsy

that begins in infancy.

Prof. Ohad Birk, of the National Institute for Biotechnology in the Negev, who

also heads the Genetics Institute at the Soroka Medical Center and The

Kahn Lab of Human Genetics, at Ben-Gurion University (BGU) of the Negev

determined that the defect is associated with the production of the 21st amino

acid, selenocysteine (SEC), which leads to progressive brain atrophy.

" The full name of the disease is Progressive Cerebro-Cerebellar Atrophy (PCCA),

in which there is a genetically-determined, progressive wasting away of cells

throughout the brain, " Birk tells ISRAEL21c, adding that " affected individuals

have psychomotor retardation which is severe by one to two years of age, and

spasticity (stiffness of the body, especially arms and legs). Most also have

epilepsy. "

Prenatal screening may lead to prevention

According to Birk, " One out of every 40 Jews of both Moroccan and Iraqi ancestry

may be carriers of this mutation, and it is estimated that in Israel there are

about 200 cases of the disease. As the disease is both severe and common,

testing for these mutations is expected to become a routine prenatal genetic

screening test in these two populations, enabling prevention of future cases. "

Explaining the significance of his research results to couples at risk, Birk

says that " if both parents are found to be carriers of a mutation in the gene,

they are at 25 percent risk for the disease in each child. They can opt to be

tested by chorionic villi sampling (CVS) as of week 10 of the pregnancy or by an

amniotic fluid test as of week 16... Another option is to undergo in-vitro

fertilization (IVF) with pre-implantation genetic diagnosis (PGD) at day one or

two of the pregnancy, and implant in the mother's womb an embryo that has been

tested to be disease free... these options are offered to every couple at risk,

and in Israel all the procedures are fully covered by the public health system.

" We assume that once the testing for mutations in this gene is implemented in

genetics institutes throughout the world, many cases will be revealed in other

countries, " he explains.

It is also believed that further research will identify these other mutations in

the same gene as the cause of mental retardation with epilepsy in additional

communities.

As the disease is progressive, elucidation of its molecular mechanisms may open

new venues to treatment, preventing disease progression. Or in other words says

the professor, " We have identified the amino acid (the protein building block)

that is missing in these patients. One can think of conceiving ways to supply

the missing building block. "

Defective amino acid leads to malfunction

The human genetic code, as deciphered some 50 years ago, encodes 20 amino acids

which are the building blocks of all proteins in the human body. However, in

recent years it became apparent that a 21st amino acid exists. Known as

Selenium, it enters the body via food and is incorporated in human tissues into

what is known as selenocysteine.

Professor Ohad Birk

Professor Ohad Birk, head of the Genetics Institute at the Soroka Medical Center

and The Kahn Lab of Human Genetics at Ben-Gurion University of the Negev.

This 21st amino acid is unique in that it is encoded by what is normally a stop

codon - that is, a DNA sequence that normally instructs the protein-building

system to end the chain of amino acids, terminating the generated protein. In

contrast with most genes, some 25 genes have a unique component that manipulates

the stop codon so that instead of terminating the evolving protein chain, it

inserts an SEC building block at that point.

" SEC is an amino acid that is a building block which is essential in the

formation of some 25 proteins in our bodies, many of which are essential for

normal brain function, " Birk tells ISRAEL21c. " The mutation in the affected

individuals prevents the formation of SEC. In the absence of SEC, the 25

proteins do not form normally, leading to severe malfunction of the brain. "

The research was conducted by Birk, his Ph.D. student Orly Agamy, and Drs.

Bruria Ben Zeev, Tally Sagie, Dorit Lev and Dieter Soll. It was funded by the

Kahn Family Fund, the Legacy Heritage Fund and the Israel Science

Foundation and published recently in the American Journal of Human Genetics.

A little research about the researcher reveals that this most serious scientist

is also blessed with a sense of humor. A click on a myspace page in his name

leads to an intriguing blog entry that begins thus: " Minimal bio: Born, raised

and will die. Detailed bio: Born, raised, played piano, wrote music. Fell in

love, made love, had kids. Loves wife, loves kids. Seeing patients. Doing

research. Teaching students. Helping some. Discovering some. Entertaining some.

Music: Writing music and texts, playing piano/keyboard + musical arrangements. "