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Cause of Progeria's Premature Aging Found

Cause of Progeria's Premature Aging Found John Tacket is an extremely rare teenager, although his list of hobbies, including billiards and drumming, is completely normal. For one thing, he appears happy and well-adjusted. Even more unusual, though, is that at 15 years, Tacket has already exceeded his predicted life expectancy by about two years. His body, from the cellular level on up, is aging far too quickly. The cause: Hutchinson-Gilford progeria syndrome, a rare genetic disorder. Research spearheaded by parents of another child with progeria has now pinpointed the origin of Tacket's premature aging: a single nucleotide error in the single sperm that (in combination with an ovum) produced him. The DNA misspelling occurs in a linchpin gene, LMNA, which codes for the molecular scaffolding that stiffens the nucleus of all cells (published on April 25 in the online edition of Nature [http://www.nature.com]) . John Tacket, the Youth Ambassador for the Progeria Research Foundation, flanked by his parents, Troy and Lynn Tacket, and National Human Genome Research Institute director Francis Collins, MD, PhD, laud the discovery of the cause of the premature aging that is the hallmark of progeria. (Photo credit: Maggie Bartlett, NHGRI) At a press conference announcing the finding, Francis Collins, MD, PhD, director of the National Human Genome Research Institute, Bethesda, Md, explained the discovery using a slide of fluorescent, misshapen cells. "You can see the dramatic consequences of having one letter out of place in the three billion letter ‘book of life'," Collins said. "After many cell divisions, the situation is not stable," he said, and the nucleus becomes "blebbed." "So it's not surprising that you get premature aging," he said. Exceedingly rare, with an incidence of about 1 case per 8 million births, progeria is typically diagnosed within the first two years of life. Symptoms include failure to grow, delayed dentition, hair loss, and sclerodermatous skin. In nearly all cases, early death is caused by a hardening of the arteries that leads to heart failure or stroke—a scenario that closely parallels normal aging. That similarity caused a buzz during the press conference. "It would be surprising if this dramatic finding doesn't apply to normal aging," said Collins. Just go do it Just go do it The scientific journey that led to the discovery began in 1998, when Leslie Gordon, MD, PhD, and her husband Scott Berns, MD, MPH, a pediatric emergency physician, learned that their 21-month-old son Sam (now 6 years old) had progeria. Gordon was on her way to becoming a pediatric ophthalmologist, but began channeling her attention to the disorder. Just go do it "I had to learn everything," she said. "And my husband and I were flabbergasted that there was almost nothing out there." A literature review had turned up fewer than 100 articles, less than one for each year since an English physician first described the condition in 1886. Just go do it So, Gordon said, she decided to "just go do it" herself. In 1999, Gordon and Berns founded the Progeria Research Foundation Inc. In 2000, the foundation secured language in the Children's Health Act that required the National Institutes of Health (NIH) to pursue progeria research. That legislation led to a formal partnership and the Progeria Research Foundation Genetics Consortium. The latter grew out of a November 2001 scientific meeting of more than 40 researchers. Just go do it Research findings quickly followed, in large part thanks to the foundation's bank of cells from progeria patients, a project directed by Gordon. Because the condition is so rare, with fewer than 50 cases known worldwide, Gordon knew that researchers would need raw material for genetic research. So she secured grants from several sources which enabled the Progeria Research Foundation to develop a bank of cells from 20 patients and their parents. Vital clues Vital clues The cell bank proved its worth almost immediately. First, experiments on cells from two patients uncovered a genetic abnormality in a particular stretch of chromosome 1. A set of cells from another patient with progeria provided the second vital clue. These cells were missing a chunk of DNA—nearly 6 million base-pairs, as reported by W. Ted Brown, MD, PhD, chairman of the department of human genetics at the New York State Institute for Basic Research in Developmental Disabilities (Am J Clin Nutr. 1992;55:1222S-1224S). Somehow, a chunk of chromosome 1 was just gone. Vital clues Knowing that such genetic glitches in the same chromosome in patients with progeria was likely to be more than a coincidence, Gordon and her colleagues mapped the suspect areas. They found that these areas overlapped on a section of chromosome 1 containing about 80 known genes—drastically narrowing the search for a progeria-related gene. Vital clues "That's when lamin A popped out at us," said Gordon. Several diseases had already been linked to mutations in the LMNA gene, which encodes two proteins, lamin A and lamin C, which are constituents of the membrane of the cell nucleus. These diseases include a type of muscular dystrophy characterized by progressive muscle wasting and cardiomyopathy. Even more intriguing, though, was the gene's connection to Dunnigan partial lipodystrophy, in which patients lose their fat deposits as they age, leading to gauntness. And, just as in progeria, the brain is left untouched. Vital clues Direct DNA sequencing of LMNA in samples from 23 patients pinpointed the problem. In the vast majority of cases, a single cytosine nucleotide had been replaced by a thymine nucleotide. This finding was independently confirmed by a group in Marseilles, France, in a research letter in published on April 17 in the online edition of Science (http://www.sciencemag.org/). Vital clues The point mutation found by both groups occurs at a particularly bad place. It creates a "cryptic splice," a mutant transcript of the LMNA that deletes 150 base pairs. The resulting protein, missing 50 amino acids, cannot support the nucleus, leading to the floppy shapes on Collins' slides. Vital clues Tests on the parents of 11 patients with progeria failed to turn up the same mutation, confirming that the disease is not inherited in the traditional sense. This finding, coupled with evidence that the mutation appears to occur only on the father's copy of the gene, led to the only logical conclusion: the mutation arises during sperm development. The genetic machinery reading a good copy of LMNA mistakes a cytosine for a thymine—the most common genetic misspelling, due to the base pairs' chemical similarity—and the genetic "spellchecker," as Collins puts it, fails to recognize the mistake. Vital clues Through a bewildering combination of bad luck, the sperm with the miscopied LMNA goes on to fertilize the mother's ovum. As a result, all the cells in the body of a patient with progeria contain the mutant form of the lamin A gene. Searching for long-life genes Searching for long-life genes Now that the mutation responsible for most cases of progeria has been found, the Progeria Research Foundation is well on its way to developing a diagnostic testing facility. In addition, a search for drugs that may correct the broken protein is already under way. Searching for long-life genes "Maybe there's [a compound or drug] already out there that can turn the lumpy-bumpy nucleus into a normal nucleus," said Collins. Searching for long-life genes As for insight into normal aging, in a study of 250 centenarians funded by the NIH, investigators are searching for variations in LMNA that may promote long life. Other research is focused on understanding how mutations in the gene lead to atherosclerosis. And Gordon is spreading the word that the Progeria Research Foundation cell bank is open to all interested researchers. Searching for long-life genes After Collins helped diminutive Tacket—the Progeria Research Foundation's Youth Ambassador—onto a chair at the press conference podium, the teenager expressed a hope shared by Gordon and the other researchers. "This is the first step and we're all looking forward to the second step, a cure," said Tackett. "Until then, I live my life to the fullest, like any other kid." Hutchinson-Gilford Progeria Syndrome Hutchinson-Gilford Progeria Syndrome Cause A mutation in the LMNA gene, resulting in a defective form of a protein called lamin A. Hutchinson-Gilford Progeria Syndrome Clinical Features Dwarfism; baldness; small face and jaw relative to head size; delayed tooth formation; aged-looking skin; joint problems; atherosclerosis and cardiovascular problems, leading to death by stroke or heart attack. Average life span is about 13 years. Hutchinson-Gilford Progeria Syndrome Diagnosis Traditionally based on individual's physical appearance. Diagnostic genetic testing is expected to become available in the near future. Hutchinson-Gilford Progeria Syndrome Treatment No specific treatment currently available. A search for drugs to treat the condition is under way. Hutchinson-Gilford Progeria Syndrome Web Links Progeria Research Foundation Inc. At: http://www.progeriaresearch.org/. Hutchinson-Gilford Progeria Syndrome Network. At: http://www.hgps.net. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Cause of Progeria's Premature Aging Found

Vastag, Brian
JAMA , Volume 289 (19) – May 21, 2003
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Publisher
American Medical Association
Copyright
Copyright © 2003 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.289.19.2481
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Abstract

John Tacket is an extremely rare teenager, although his list of hobbies, including billiards and drumming, is completely normal. For one thing, he appears happy and well-adjusted. Even more unusual, though, is that at 15 years, Tacket has already exceeded his predicted life expectancy by about two years. His body, from the cellular level on up, is aging far too quickly. The cause: Hutchinson-Gilford progeria syndrome, a rare genetic disorder. Research spearheaded by parents of another child with progeria has now pinpointed the origin of Tacket's premature aging: a single nucleotide error in the single sperm that (in combination with an ovum) produced him. The DNA misspelling occurs in a linchpin gene, LMNA, which codes for the molecular scaffolding that stiffens the nucleus of all cells (published on April 25 in the online edition of Nature [http://www.nature.com]) . John Tacket, the Youth Ambassador for the Progeria Research Foundation, flanked by his parents, Troy and Lynn Tacket, and National Human Genome Research Institute director Francis Collins, MD, PhD, laud the discovery of the cause of the premature aging that is the hallmark of progeria. (Photo credit: Maggie Bartlett, NHGRI) At a press conference announcing the finding, Francis Collins, MD, PhD, director of the National Human Genome Research Institute, Bethesda, Md, explained the discovery using a slide of fluorescent, misshapen cells. "You can see the dramatic consequences of having one letter out of place in the three billion letter ‘book of life'," Collins said. "After many cell divisions, the situation is not stable," he said, and the nucleus becomes "blebbed." "So it's not surprising that you get premature aging," he said. Exceedingly rare, with an incidence of about 1 case per 8 million births, progeria is typically diagnosed within the first two years of life. Symptoms include failure to grow, delayed dentition, hair loss, and sclerodermatous skin. In nearly all cases, early death is caused by a hardening of the arteries that leads to heart failure or stroke—a scenario that closely parallels normal aging. That similarity caused a buzz during the press conference. "It would be surprising if this dramatic finding doesn't apply to normal aging," said Collins. Just go do it Just go do it The scientific journey that led to the discovery began in 1998, when Leslie Gordon, MD, PhD, and her husband Scott Berns, MD, MPH, a pediatric emergency physician, learned that their 21-month-old son Sam (now 6 years old) had progeria. Gordon was on her way to becoming a pediatric ophthalmologist, but began channeling her attention to the disorder. Just go do it "I had to learn everything," she said. "And my husband and I were flabbergasted that there was almost nothing out there." A literature review had turned up fewer than 100 articles, less than one for each year since an English physician first described the condition in 1886. Just go do it So, Gordon said, she decided to "just go do it" herself. In 1999, Gordon and Berns founded the Progeria Research Foundation Inc. In 2000, the foundation secured language in the Children's Health Act that required the National Institutes of Health (NIH) to pursue progeria research. That legislation led to a formal partnership and the Progeria Research Foundation Genetics Consortium. The latter grew out of a November 2001 scientific meeting of more than 40 researchers. Just go do it Research findings quickly followed, in large part thanks to the foundation's bank of cells from progeria patients, a project directed by Gordon. Because the condition is so rare, with fewer than 50 cases known worldwide, Gordon knew that researchers would need raw material for genetic research. So she secured grants from several sources which enabled the Progeria Research Foundation to develop a bank of cells from 20 patients and their parents. Vital clues Vital clues The cell bank proved its worth almost immediately. First, experiments on cells from two patients uncovered a genetic abnormality in a particular stretch of chromosome 1. A set of cells from another patient with progeria provided the second vital clue. These cells were missing a chunk of DNA—nearly 6 million base-pairs, as reported by W. Ted Brown, MD, PhD, chairman of the department of human genetics at the New York State Institute for Basic Research in Developmental Disabilities (Am J Clin Nutr. 1992;55:1222S-1224S). Somehow, a chunk of chromosome 1 was just gone. Vital clues Knowing that such genetic glitches in the same chromosome in patients with progeria was likely to be more than a coincidence, Gordon and her colleagues mapped the suspect areas. They found that these areas overlapped on a section of chromosome 1 containing about 80 known genes—drastically narrowing the search for a progeria-related gene. Vital clues "That's when lamin A popped out at us," said Gordon. Several diseases had already been linked to mutations in the LMNA gene, which encodes two proteins, lamin A and lamin C, which are constituents of the membrane of the cell nucleus. These diseases include a type of muscular dystrophy characterized by progressive muscle wasting and cardiomyopathy. Even more intriguing, though, was the gene's connection to Dunnigan partial lipodystrophy, in which patients lose their fat deposits as they age, leading to gauntness. And, just as in progeria, the brain is left untouched. Vital clues Direct DNA sequencing of LMNA in samples from 23 patients pinpointed the problem. In the vast majority of cases, a single cytosine nucleotide had been replaced by a thymine nucleotide. This finding was independently confirmed by a group in Marseilles, France, in a research letter in published on April 17 in the online edition of Science (http://www.sciencemag.org/). Vital clues The point mutation found by both groups occurs at a particularly bad place. It creates a "cryptic splice," a mutant transcript of the LMNA that deletes 150 base pairs. The resulting protein, missing 50 amino acids, cannot support the nucleus, leading to the floppy shapes on Collins' slides. Vital clues Tests on the parents of 11 patients with progeria failed to turn up the same mutation, confirming that the disease is not inherited in the traditional sense. This finding, coupled with evidence that the mutation appears to occur only on the father's copy of the gene, led to the only logical conclusion: the mutation arises during sperm development. The genetic machinery reading a good copy of LMNA mistakes a cytosine for a thymine—the most common genetic misspelling, due to the base pairs' chemical similarity—and the genetic "spellchecker," as Collins puts it, fails to recognize the mistake. Vital clues Through a bewildering combination of bad luck, the sperm with the miscopied LMNA goes on to fertilize the mother's ovum. As a result, all the cells in the body of a patient with progeria contain the mutant form of the lamin A gene. Searching for long-life genes Searching for long-life genes Now that the mutation responsible for most cases of progeria has been found, the Progeria Research Foundation is well on its way to developing a diagnostic testing facility. In addition, a search for drugs that may correct the broken protein is already under way. Searching for long-life genes "Maybe there's [a compound or drug] already out there that can turn the lumpy-bumpy nucleus into a normal nucleus," said Collins. Searching for long-life genes As for insight into normal aging, in a study of 250 centenarians funded by the NIH, investigators are searching for variations in LMNA that may promote long life. Other research is focused on understanding how mutations in the gene lead to atherosclerosis. And Gordon is spreading the word that the Progeria Research Foundation cell bank is open to all interested researchers. Searching for long-life genes After Collins helped diminutive Tacket—the Progeria Research Foundation's Youth Ambassador—onto a chair at the press conference podium, the teenager expressed a hope shared by Gordon and the other researchers. "This is the first step and we're all looking forward to the second step, a cure," said Tackett. "Until then, I live my life to the fullest, like any other kid." Hutchinson-Gilford Progeria Syndrome Hutchinson-Gilford Progeria Syndrome Cause A mutation in the LMNA gene, resulting in a defective form of a protein called lamin A. Hutchinson-Gilford Progeria Syndrome Clinical Features Dwarfism; baldness; small face and jaw relative to head size; delayed tooth formation; aged-looking skin; joint problems; atherosclerosis and cardiovascular problems, leading to death by stroke or heart attack. Average life span is about 13 years. Hutchinson-Gilford Progeria Syndrome Diagnosis Traditionally based on individual's physical appearance. Diagnostic genetic testing is expected to become available in the near future. Hutchinson-Gilford Progeria Syndrome Treatment No specific treatment currently available. A search for drugs to treat the condition is under way. Hutchinson-Gilford Progeria Syndrome Web Links Progeria Research Foundation Inc. At: http://www.progeriaresearch.org/. Hutchinson-Gilford Progeria Syndrome Network. At: http://www.hgps.net.

Journal

JAMA – American Medical Association

Published: May 21, 2003

Keywords: premature aging syndrome,progeria

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