Cracking The Code

In detecting the defective gene responsible for childhood ageing, 

two studies hope to find variants of the gene associated with longevity, reports Biplab Das 

The long-standing puzzle of childhood ageing has been cracked. Two studies have detected a defective gene in children suffering from premature ageing. "It is the first piece in solving the tragic fate of such children," says Francis Collins, director of the National Human Genome Research Institute in Bethedsa, Maryland, who led one of the studies released online in the latest issue of the journal Nature. This disease is called the Hutchinson Gilford Progeria Syndrome, also known as progeria. 

According to the researchers, the discovery of the syndrome's genetic basis will aid the development of tests and therapies for the disease. It was first diagnosed in 1886. Since then, 100 cases of HGPS have been recorded worldwide. It affects one in eight million newborns worldwide. The affected children age up to five to 10 times faster than normal children do. They develop pinched and wrinkled skin, lose hair and grow slowly. Furthermore, they are prone to ailments like stiff joints and hip dislocation, which are common among the elderly. By the age of 13, most of them die from heart attacks or strokes. 

Children with HGPS suffer from severe muscle pain, says Nicolas Levy of the Timone Hospital in Marseille, France, co-author of the second study released online in the latest issue of the journal, Science. Between them, the two groups studied 21 patients. They homed in on the chromosome where the defective gene resides. The normal copy of the defective gene has been found to encode two proteins, lamin A and lamin C. Together with lamin B, these proteins form a wallpaper like meshwork in the inner linning of the membrane that surrounds the cell's nucleus. 

The researchers from the National Human Genome Research Institute found that 18 patients had a substitution of a single DNA base in the defective gene. The DNA molecule has a shape like a twisted staircase. The steps of the staircase are made of four bases like adenine, guanine, cytosine and thymine. The bases remain paired up with each other, adenine with thymine and guanine with cytosine. Now, a long string of base pairs form a gene, which, in turn, codes for a definite protein. So genes contain the recipe for making proteins. Removing or replacing a single base can change the recipe, changing its end products, proteins. 

The culprit gene for premature ageing had faced the similar fate. The LMNA gene, named after the proteins it codes, has a change from cytosine (C) to thymine (T). One of the patients had guanine (G) substituted by adenine (A) in the LMNA gene. Cells with defective gene produce deformed lamin proteins, distorting the nuclear membrane's normal shape. 

The NGHRI team also found that an abnormal lamin A protein had 50 amino acids missing at one end of its structure. Such proteins hinder normal cell growth. And the cells die prematurely, impairing the tissues' ability to regenerate. In every case, the parents were normal, indicating that the alteration of a single base was a new mutation in the child. To study the effect of abnormal lamin A protein on cells, the team used fluorescent antibodies to track lamin A in skin cells taken from progeria patients, as well as unaffected people. The study showed that about half the cells from progeria patients had misshapen nuclear membranes. 

"This instability of the nuclear membrane may pose major problems for tissues subjected to intense physical stress - such as those found in the cardiovascular and musculoskeletal systems, which are severely damaged in progeria," says Maria Erikson, a post-doctoral fellow in Collins's lab and a member of the team. "Initially, we could hardly believe that such a small change in the gene was the culprit. How could this bland-looking mutation have such terrible consequences in the body?" 

Thanks to the Human Genome Project, which opened up such possibilities of exploring the molecular roots of diseases, "free and unrestricted access to human genome sequence is greatly speeding the pace of disease gene discovery," says Collins. "Finding the gene for progeria would have been impossible without the tools provided by HGP." 

The promising aspect of the new findings is the prospect of a therapy for progeria patients. In fact, researchers plan to study the possibility that statin or other drugs known to inhibit a step in protein processing might reduce the production of abnormal lamin proteins in progeria patients. This new discovery may also uncover many secrets of the normal ageing process. This is why the researchers plan to have a close look at the LMNA genes of people who are exceptionally long-lived in the hope of finding any variants of the gene associated with longevity. But it is still long way to go before affected children can reap a benefit from this discovery. 

Collins summed up the current situation. "It is impossible to predict how soon our findings will translate into treatments for children suffering from progeria. Unfortunately, as we have witnessed with other genetic discoveries, the road from the lab to the clinic is not always swift or smooth."