News Tips from Annual Meeting of the American Society of Human Genetics

Newswise — DISCOVERY OF NEW GENE ASSOCIATED WITH ALZHEIMER'S DISEASE(Scheduled for presentation at 4:30 p.m. CDT, Tuesday, Oct. 10; poster presentation #2034, Hall D/E, Ernest N. Morial Convention Center.)

Researchers at Johns Hopkins have identified what might be a second gene that signals risk for late-onset Alzheimer's disease. As many as 4.5 million Americans are believed to have AD, a disabling and fatal disorder marked by memory loss, trouble with language and difficulty performing familiar tasks.

Late-onset AD occurs after age 65. While three genes are known to cause an early-onset form, only one other gene has been shown to be a risk factor for the late-onset form.

Hunting for genes that are turned on or off in AD patients, the Hopkins researchers identified a gene on chromosome 10 that they call ASAH2L, which, interestingly, appears to exist only in humans and appears less active in AD patients. The gene also appears less active in women and with advancing age, which are risk factors for developing AD. According to the researchers, ASAH2L seems to have arisen from an accidental duplication of another nearby gene.

Although the exact role of the ASAH2L gene in AD is not yet clear, the investigators think it might be involved in keeping brain cells from dying. Says Dimitrios Avramopoulos, M.D., Ph.D., an assistant professor of psychiatry and behavioral sciences at Hopkins, "Hopefully it will lead to developing more treatment options in the future."

NOT ALL INHERITED CANCER RISK IS IN THE GENES(Scheduled for presentation at 11 a.m. CDT, Wednesday, Oct. 11; Hall F, Ernest N. Morial Convention Center.)

Researchers at Johns Hopkins have developed a mouse model for studying how DNA changes that occur outside of genes can increase the frequency of colon tumors. Unlike changes in the DNA sequences of genes themselves, so-called epigenetic changes include alterations in the pattern of chemical groups attached to DNA. Another type of epigenetic change, known as loss of imprinting, inactivates one copy of a gene based on which parent that copy came from. Loss of imprinting already has been linked to disease risk, including cancer.

Mice engineered to carry a mutation in a gene called Apc are more likely to develop a form of inherited colon cancer. The Hopkins team found that when these same mice lose imprinting of a second gene, called IGF2, they develop more tumors than their normal littermates.

Studies of the colon stem cells in these doubly mutant mice also reveal changes in how these cells behave, suggesting that epigenetic changes might predispose certain cells to develop into tumors.

"Loss of IGF2 imprinting is common in humans, too, and already associated with a family history of colorectal cancer and increased frequency of colon tumors," says Andrew Feinberg, M.D., M.P.H., the King Fahd Professor of Medicine and professor of molecular biology and genetics at Hopkins' Institute of Basic Biomedical Sciences. "It may be possible to develop a screen for colon cancer risk by looking at the epigenetic changes in colon cells of healthy people."

In fact, as IGF2 imprinting predisposes people to colon cancer, other epigenetic changes may predispose people to other diseases. Feinberg suggests that studying epigenetic changes across the entire human genome may be useful in measuring disease risk.

ALBINISM CAN BE ASSOCIATED WITH OTHER HEALTH RISKS(Scheduled for presentation at 10:30 a.m. CDT, Thursday, Oct. 12; poster presentation #592, Hall D/E, Ernest N. Morial Convention Center.)

Researchers at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins are investigating how often patients who lack the ability to make skin pigment can also be affected with other inherited disorders, specifically Angelman syndrome or Prader-Willi syndrome.

The most common cause of albinism among Africans or African-Americans is a deletion in a gene known as OCA2. The OCA2 gene is located on chromosome 15 within a much larger region that is deleted in Angelman syndrome and Prader-Willi syndrome. Angelman syndrome is characterized by severely impaired speech, mental retardation, seizures and difficulty moving; Prader-Willi syndrome is marked by retardation, weak muscle tone, obesity and short stature. Patients with albinism alone do not have any of the features of Angelman or Prader-Willi.

The research team started the study after evaluating a 17-month old-African girl with albinism who also showed tremors and lack of speech development. Study of her DNA revealed that she indeed carried not only a deletion in one copy of her OCA2 gene, but also a second large deletion associated with Angelman syndrome. To have both albinism and either Angelman or Prader-Will syndrome, one must have an abnormal copy of the OCA2 gene on one chromsome 15, and on the other chromosome 15 carry the larger Angelman/Prader-Willi deletion.

Prompted by this result, the research team surveyed a database of more than 30,000 families in a Johns Hopkins clinical database and found 49 of them to have albinism. Of these 49, eight also had features that were suggestive of either Angelman syndrome or Prader-Willi syndrome but are not known to have been diagnosed with these conditions.

This information is an important warning for doctors treating patients with albinism to investigate further for the presence of other health problems. About 1 in 10,000 African Americans are affected with albinism -- characterized by decreased pigmentation in hair, skin and eyes.

"Most people affected with albinism alone do not have these other conditions," assures Julie Hoover-Fong, M.D., assistant professor of pediatrics at the McKusick-Nathans Institute of Genetic Medicine at Hopkins. "But if a patient walks into the clinic with albinism and other features like seizures or obesity, the physician should consider the additional diagnoses of Angelman or Prader-Willi syndrome. These patients should undergo additional tests for diagnosis and proper treatment."