CMT 1A news: Big genome changes lead to nervous system disorders

[Guest guest]

Big genome changes lead to nervous system disorders

http://www.bcm.edu/news/item.cfm?NewsID=712

HOUSTON -- (October 4, 2006) -- Understanding many nervous system

disorders means taking the large view of the human genome, looking

beyond small changes in the sequence of DNA, and identifying

structural variations such as deletions or additions of large chunks

of genetic material, said Baylor College of Medicine researchers in a

review that appears in the current issue of the journal Neuron.

In fact, said Dr. Lupski, professor of molecular and human

genetics and pediatrics at BCM, many nervous system disorders are

associated with extra copies of genes or deletions of large chunks of

the genome that can affect the amount of protein produced associated

with a particular gene.

In the paper, co-authored by graduate student Lee, the two

scientists describe neurodevelopmental, neurodegenerative, behavioral

and psychiatric disorders known or believed to result from these

large genomic changes. These large changes can result in extra copies

of genes being present in the genome or deletions of genes, which can

affect the amount of circulating protein associated with the disease.

One advance that makes it easier to study such changes is the

development of DNA microarrays that enable researchers to scan an

entire human genome at once at higher resolution than previously

possible with a microscope. While DNA sequencing looks at each base

pair, these microarrays or gene chips allow scientists to evaluate

thousands of bases or megabases at once, identifying large

differences in the structure of genetic material.

In fact, said Lupski, the first disease in which this was identified

in his lab was Charcot-Marie Tooth in which variation in the number

of copies of a gene called PMP22 can cause different forms and

severity of the neurodegenerative disorder.

" We can now identify several instances wherein changes in the normal

two copies of a gene – one from Mom and one from Dad – can result in

a clinical disease phenotype (or symptoms), " said Lupski.

" These larger structural changes can even be associated with

behavioral disorders or psychiatric traits, " said Lee.

This copy number variation thesis could explain the question as to

why people could inherit a gene but not show signs of the disease

until they are 40 or 50 years old. Parkinson's disease is a case in

point.

" There is a tremendous amount of structural variation in the human

genome, " said Lupski. In some cases, the structural changes or

variations in the number of genes may not have an effect, but in

others it could be involved in susceptibility to disease.

In other cases, he said, a woman may have one chunk of her genome

missing and marry a man with another chunk gone. They themselves may

not have a disease, but the child they produce might because he or

she inherited both structural variants.

Understanding this may change the way scientists study diseases, he

said. If a genomic disorder results from altered gene dosage, it may

be possible to intervene therapeutically by correcting the gene

dosage.

" When you study an 85-year-old with Alzheimer's disease, you don't

just look at the base pair changes. You look at the structural

changes in the genome, " he said.

Lupski is also vice chair of the BCM department of molecular and

human genetics. Other disorders discussed in the paper include:

Charcot-Marie-Tooth disease type 1A, -Beuren Syndrome, -

Dieker Syndrome and Lissencephaly, Angelman and Prader-Willi

syndromes, -Magenis Syndrome, Neurofibromatosis Type 1, spinal

muscular atrophy (SMA), and Alzheimer's disease.