progeria

Problems With Nuclear Membrane Could Play Part in Heart Disease, Leukemia, and Progeria

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Researchers at Salk University have completed a study that’s revealed how the nucleus acts on its contents in order to influence gene expression. They discovered that nuclear core components regulate the expression of cell identity genes through the interaction with super-enhancers. Salk Professor, Martin Hetzer, comments “Our research shows that, far from being a passive enclosure as many biologists have thought, the nuclear membrane is an active regulatory structure.”

The team discovered two particular proteins are actively associated with the parts of DNA known to trigger the expression of genes. By better understanding the way in which these proteins function, scientists gain a better insight into diseases that are linked to dysfunctional nuclear membrane components including heart disease, leukemia and some aging disorders such as progeria. The first author of the paper and a Salk staff scientist, Arkaitz Ibarra said, “Discovering that key regulatory regions of the genome are positioned at nuclear pores was very unexpected.”

Salk scientists discover that nuclear pore components regulate the expression of cell identity genes through functional interactions with super-enhancers. In the image, a super-enhancer driven cell identity gene (red dot) localizes in close proximity to the nuclear envelope (green) in the nucleus of human primary lung fibroblasts (blue). Click here for a high-resolution image Credit: Salk Institute
Salk scientists discover that nuclear pore components regulate the expression of cell identity genes through functional interactions with super-enhancers. In the image, a super-enhancer driven cell identity gene (red dot) localizes in close proximity to the nuclear envelope (green) in the nucleus of human primary lung fibroblasts (blue).

Next, the team studied a human bone cancer cell line to see which areas of DNA interacted with nucleoporins. They pinpointed where two nucleoporins (Nup153 and Nup93) came in contact with the genome and looked into which genes were being affected and how. It was found that Nup153 and Nup93 both interacted with super-enhancers that are vital in determining cell identity and driving gene expression. Hetzer says, “People have thought the nuclear membrane is just a protective barrier, which is maybe the reason why it evolved in the first place. And it’s such an important area because so far, every membrane protein that has been studied and found to be mutated or mislocalized seems to cause a human disease.”

Werner syndrome

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Werner syndrome (also called progeria) is a hereditary condition associated with premature aging and an increased risk of cancer and other diseases. Signs of Werner syndrome usually develop in the teenage years. A person with Werner syndrome does not have the usual growth spurt typical of a teenager and is shorter on average. Signs of aging, including gray hair and hair loss, may appear in the 20s. Cataracts, type 2 diabetes, and osteoporosis (decrease in bone mineral density) may develop in the 30s. One of the most significant health problems faced by people with Werner syndrome is the early development of atherosclerosis, commonly known as hardening of the arteries, which can lead to a heart attack.

What causes Werner syndrome?

Werner syndrome is a genetic condition. This means that the risk of Werner syndrome can be passed from generation to generation in a family. Mutations (alterations) in the WRN gene are known to cause Werner syndrome. Research is ongoing to learn more about Werner syndrome.

How is Werner syndrome inherited?

Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. Werner syndrome follows an autosomal recessive inheritance pattern, which means that a mutation must be present in both copies of the gene for a person to be affected. This means that both parents must pass on a gene mutation for a child to be affected. A person who has only one copy of the gene mutation is called a carrier. When both parents are carriers of a recessive gene mutation, there is a 25% chance that a child will inherit two mutations and be affected.

How common is Werner syndrome?

Werner syndrome is considered to be very rare. It is estimated that one in 200,000 people in the United States may have Werner syndrome. Werner syndrome is somewhat more common in Japan, where it is estimated that one in 30,000 people may have the condition.

How is Werner syndrome diagnosed?

Currently, the diagnosis of Werner syndrome is suspected if someone has several of the features that have been reported in people with this condition.

Common features of Werner syndrome (diagnosed after age 10):

  • Cataracts in both eyes (bilateral)
  • Skin changes associated with aging
  • Characteristic facial features, including wrinkling and loss of muscle tone
  • Short stature (height)
  • Early graying or thinning of the hair
  • Family history of Werner syndrome
  • Positive 24-hour urine hyaluronic acid test

Other features seen in Werner syndrome:

  • Type 2 diabetes
  • Decreased fertility
  • Osteoporosis
  • Cancer
  • Bone changes in the fingers and toes
  • Tissue changes
  • Early atherosclerosis (plaque build up in arteries)
  • Hoarse or high-pitched voice
  • Flat feet

Guidelines for the diagnosis of Werner syndrome have been proposed but may change over time as more is learned about this condition. Genetic testing for mutations in the WRN gene is available only as part of research studies (clinical trials). Mutations in the WRN gene are found in about 90% of people with Werner syndrome.

What are the estimated cancer risks associated with Werner syndrome?

The risk of cancer is increased in people who have Werner syndrome, but the specific risk of cancer is unknown. Types of cancers reported in people with Werner syndrome include thyroid cancer, melanoma, soft tissue sarcoma, and osteosarcoma (bone cancer).

What are the screening options for Werner syndrome?

Suggested screenings for people diagnosed with Werner syndrome include:

  • Yearly screening for type 2 diabetes
  • Yearly lipid profile (blood test)
  • Yearly eye examination to look for signs of cataracts
  • Yearly physical and dermatological (skin) examinations to screen for cancers associated with Werner syndrome

People with Werner syndrome should also avoid smoking, be physically active, and maintain a healthy weight to help decrease the risk of heart disease. Any chest pains (also known as angina) should be carefully evaluated by a doctor. Due to the risk of skin cancer, people with Werner syndrome should also limit sun exposure and use skin protection when outside.

Screening recommendations may change over time as new technologies are developed and more is learned about Werner syndrome. It is important to talk with your doctor about appropriate screening tests.

source: mayo clinic house call