Ehlers-Danlos syndrome refers to several disorders of collagen, the connective tissue protein that comprises much of the human body. In Ehlers-Danlos syndome type IV, also called the "vascular type," various structures can suddenly rupture most commonly arteries, intestines, and uteruses. Average age at death is 48. Other symptoms include easy bruising, thin skin, and distinctive facial features.

The mutation that causes Ehlers-Danlos syndrome type IV is in a gene called COL3A1. The condition is autosomal dominant, and it is variably expressive. Collagen is normally a triple helix, cut from a longer molecule called procollagen. Overall it consists of many repeats of the amino acid sequences "glycine-X-Y," where X is usually proline and Y is a form of proline with a hydroxyl (OH) group added. These constituent amino acids are small, enabling the tight triple helix to form. In people with Ehlers-Danlos syndrome type IV, some of the procollagen single helices are abnormal, and these cannot associate with the normal ones. As a result, only an eighth of the collagen triple helices are normal, and this causes the symptoms, with the specific expression determined by exactly where in the body the abnormal collagen forms.

In the Maguire family, in the first generation, Bruce died at age 53 of a burst aorta (an aneurysm). He and his wife Martha had four children. Daughter Sheila bruises easily, as does her son Phil. Her brother Dan is healthy. Sister Shelley died from a ruptured uterus giving birth to son David. Brother Eric died at age 27 of a ruptured large intestine. For years the family thought that these symptoms and problems were unrelated, but a workup at a genetics clinic following Shelley’s death led to the diagnosis of Ehlers-Danlos syndome type IV. Knowledge of the diagnosis will enable other family members to be tested for weakening in certain blood vessels that can precede aneurysm.

1. Draw a pedigree of the Maguire family. (Identify unnamed individuals with numbers.)

2. Which family members should be screened for the tendency to develop aneurysms?

3. Several types of mutations can cause this condition. Many of them replace the glycine

with a larger amino acid. How does this disrupt collagen structure?

4. Studies that attempt to associate particular mutations with particular phenotypes, or

degrees of severity, have not revealed any obvious relationships for this condition.

Another factor that might determine how serious a case of Ehlers-Danlos type IV

might be is.

5. Phil is aware of the rupture problem in the family, but thinks that because his

symptom is only bruising, that he need not be concerned about his own future health,

or about passing on the gene to offspring. Is this wise? Cite a reason for your answer.

6. The evidence that Ehlers-Danlos type IV is pleiotrpic is that.

Answers

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