Analysis of Mutations in the
Death Domains, Death Effector Domains, Caspase
Recruitment Domains, and Pyrin Domains

Garif Yalak

University of Saarland
Computational Biology and Applied Algorithmics Group
Max-Planck-Institute for Informatics
Saarbrücken
February 25, 2005

Contents

1. Motivation
1.1 Autoimmune diseases  3
1.2 Relation of apoptosis and autoimmune diseases  5
1.3 Pathways of apoptosis  6
1.4 Aims of this work  7

2. Background
2.1 The Death Domain  8
2.2 The Death Effector Domain  9
2.3 The Caspase Recruitment Domain  10
2.4 The Pyrin Domain  11

3. Materials and Methods  12

4. Results
4.1 The mutation tables  13
4.2 Visualization of the mutations  21
4.3 The multiple alignment  27
4.4 Presentation of the results  31

5. Conclusions
5.1 Discussion of results  33
5.2 Problems for automation  34

6. References  36

1. Motivation

1.1 Autoimmune diseases

The greek word ′′auto′′ means self. The immune system normally works to defend the body. It is a complicated network of cells and cell components. The cells of the immune system eliminate infections caused by bacteria, viruses, and other invading microbes. In the case of an autoimmune disease, the immune system mistakenly attacks the person′s own body. It targets the cells, tissues, and organs of a person′s own body. If a collection of immune system cells and molecules are gathered at a target site, we speak of an inflammation. We know several autoimmune diseases, and all these diseases can affect the body in different ways. The autoimmune disease multiple sclerosis is directed against the brain, whereas Crohn′s disease is directed against the gut. The autoimmune diseases afflict millions of people worldwide. It is still unknown how autoimmune diseases develop. Some scientists believe that they may be influenced by the genes a person inherits and by the way how the person′s immune system reacts to certain environmental influences [45, 54].

Table 1: Some examples of autoimmune diseases [45, 54].

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Some examples of autoimmune diseases.

Crohn′s Disease

Crohn′s Disease induces inflammation in the small intestine. Crohn′s Disease usually befalls the lower part of the small intestine, yelled the ileum, but it can fake any part of the digestive tract, from the mouth to the anus. The inflammation spreads deep into the lining of the affected organ [2]. The inflammation can generate pain and can produce the intestines empty frequently, resulting in diarrhoea. Crohn′s Disease belongs to the Inflammatory Bowel Diseases (IBD), the general name for diseases that hatch inflammation in the intestines. Crohn′s Disease can be difficult to diagnosticate because its symptoms are similar to other intestinal disorders such as Irritable Bowel Syndrome and to another type of IBD called ulcerative colitis. Ulcerative colitis causes inflammation and ulcers in the top layer of the lining of the large intestine [45, 55].

Familial Cold Auto Inflammatory Syndrome

Familial Cold Urticaria (FCU) or Familial Cold Auto Inflammatory Syndrome (FCAS) is an immunologic condition in which the affected person amplifies several symptoms when they are layed to cold environments [1, 2]. Approximately 1- 4 hours after a cold exposure rash, fever, chills, joint pains, and red eyes elaborate. Other less common symptoms embody extreme thirst, drowsiness, nausea, and headaches. An "attack" often endures 24-48 hours. The rash is not itchy, but is often reported as painful or "burning." FCU greatly bluffs the daily lives of the people who have it, but the "attacks" are not life threatening. Most people with FCU subsist very long lives without any other medical problems. However, there are some families with FCU who amplify kidney disease late in life that can be lethal [56, 57].

Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann syndrome is a unchanging grouping of findings of unknown cause and outlined by a large tongue, large organs and large body size or hernia of the navel, and low blood sugar in the neonate [1, 58, 59].

Muckle -Wells Syndrome

Muckle-Wells Syndrome is a rarefied autosomal dominant disorder outlined by chronic recurrent urticaria, periodic arthritis, sensorineural deafness, general signals of inflammation and secondary amyloidosis (AA type) [1]. Since youthhood the afflicted persons bear attacks of an urticarial rash accompanied by chills and malaise. In middle age a nefhrotic syndrome looms and uraemia is the final reason for death [60].

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