Mutations and Human Disease

1. Mutations and Human Disease • Mutations- are changes in the genetic material including the DNA N-base sequences or to structure of a chromosome.

2. DNA (gene) mutations <> Any change in the DNA N-base sequence may result in an alteration of the amino acid sequence. Two types: Point Mutations-are N-base substitutionsthat usually cause a single amino acid change in a protein.

3. An example of a Point Mutation: • The dog bit the cat. • The dog bit the car. One change in a single letter can make a difference.

4. A missense mutation is a point mutation that results in a codon that Codes for a different amino acid. *Substitution

5. Sickle cell anemia is an example of a Point Mutation where a single base substitution alters the hemoglobin protein.

6. Just one DNA base has been changed. This change inserts the amino acid valine in place of glutamic acid. As a result the abnormal hemoglobin is somewhat less soluble than normal hemoglobin. A decrease in blood oxygen levels causes many of the hemoglobin molecules to come out of solution and stick together. The stuck-together molecules form long chains and fibers that produce the characteristic shape of sickled cells.

7. When oxygen levels are low, the sickled red blood cells are fragile and tend to clump together, clogging capillaries.

10. A nonsense mutation results in a premature stop codon. Usually A non functional protein product. Chain terminating

11. 2. Frameshift Mutations- are N-base additions or deletions that usually alter all the amino acids in the protein from the site of the mutation.

12.  Previous Next  Types of gene mutations A frameshift mutation changes the amino acid sequence from the site of the mutation.

15. Chromosomal Mutations • Changes to the chromosomal structure usually due to breakage during cell division. • FIVE types: • Deletion- a section is lost or deleted. • Duplication- a section is repeated. • Inversion- a section is broken out and then spliced back in incorrectly. • Translocation- a section of one chromosome attaches to a different chromosome. • Non-disjunction- failure of homologous chromosomes to separate during meiosis

16.  Previous Next  Types of gene mutations A section of DNA is accidentally duplicated when a chromosome is copied.

17. 3.Translocation: a fragment of a chromosome is moved ("trans-located") from one chromosome to another - joins a non-homologous chromosome. The balance of genes is still normal (nothing has been gained or lost) but can alter phenotype as it places genes in a new environment. Can also cause difficulties in egg or sperm development and normal development of a zygote. Acute Myelogenous Leukemia is caused by this translocation:

18. Chromosomal disorder caused by Non-disjunction (failure of homologous chromosomes to separate during meiosis):Trisomy 21= also known as Downs Syndrome.

19. Nondisjunction occurs when either homologues fail to separateduring anaphase I of meiosis, or sister chromatids fail to separate during anaphase II. The result is that one gamete has 2 copies of one chromosome and the other has no copy of that chromosome. (The other chromosomes are distributed normally.) If either of these gametes unites with another during fertilization, the result is aneuploidy (abnormal chromosome number) A trisomic cell has one extra chromosome (2n +1) = example: trisomy 21. (Polyploidy refers to the condition of having three homologous chromosomes rather then two) A monosomic cell has one missing chromosome (2n - 1) = usually lethal except for one known in humans: Turner's syndrome (monosomy XO).

21. Mutation and Human Disease Many human diseases are caused by mutations that have resulted in proteins that do not function properly. Metabolic diseases – enzymes are non functional thus interfering with normal metabolism. Transport diseases – transport proteins are missing or nonfunctional, thus interfering with cellular transport Structural disease – structural proteins are abnormal, thus interfering with normal growth and development.

22. Little People, Big World: The Roloffs (l. to r.): Zach, Matt, Amy, Jacob, Molly, and Jeremy. (2006). Matt’s type of dwarfism, diastrophic dysplasia, resulted in numerous childhood surgeries. Amy’s type is called achondroplasia, and she has had very few (if any) complications. She is 4’2”. Zach has the same disorder as his mother, but has had numerous medical complications. Zach is the twin brother to Jeremy who is of normal stature. Jacob and Molly are also of normal height.

23. Genetics of Achondroplasia Read Full Article Abstract Achondroplasia is an autosomal dominant disorder, which results in abnormal bone growth and leads to short stature. This disease occurs approximately in 1 in 25,000 births, and is common in all races. Achondroplasia is one of the oldest genetic disorders described: some of the ancient Egyptian medical texts depict patients with Achondroplasia. Achondroplasia affects bone growth, especially of the long bones of arms and legs. The meaning of the word Achondroplasia is "without cartilage". Even though in affected persons cartilage is formed, it develops into bones very slowly. This results in short stature and reduced height, approximately 1.22 meters (4'0"), in adults. Achondroplasia is usually diagnosed after birth by a physical exam and X-rays. The patients have relatively normal size torso and shortened arms, legs, fingers and toes. Babies with Achondroplasia have difficulties sitting, standing and walking without support. 99% of the affected individuals have a single point mutation in the Fibroblast Growth Factor Receptor gene 3 (FGFR 3), which is located on chromosome 4. As a result of this mutation, glycine is substituted for arginine at codon 380 of FGFR 3. Such a mutation results in an abnormal cartilage and fibrous connecting tissue formation. Therefore, not only bones, but the ligaments, tendons and muscles of the patient with Achondroplasia are affected.

24. Diastrophic dysplasia has an autosomal recessive pattern of inheritance. Diastrophic dysplasia affects about 1 in 100,000 births. Mutations in the SLC26A2gene cause diastrophic dysplasia, and it is one of a spectrum of skeletal disorders caused by mutations in the SLC26A2 gene. The protein made by this gene is essential for the normal development of cartilage and for its conversion to bone. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, but in adulthood this tissue continues to cover and protect the ends of bones and is present in the nose and external ears. Mutations in the SLC26A2 gene alter the structure of developing cartilage, preventing bones from forming properly and resulting in the skeletal problems characteristic of diastrophic dysplasia. This condition is an autosomal recessive disorder, which means the defective gene is located on an autosome, and both parents must carry one copy of the defective gene in order to have a child born with the disorder. The parents of a child with an autosomal recessive disorder are usually not affected by the disorder.

25. Acromegaly: abnormally high linear growth due to excessive insulin like growth factor 1 in adulthood. Gigantism : same disorder (IGF-1) while growth plates open during childhood. *Usually from adenoma (benign tumor) Of the pituitary gland. Severe disfigurement and premature death Andre the Giant: WWF performer and actor. Reported to be 7 feet 2 inches tall and 520 pounds. Sandy Allen in 1995. Guinness World Book’s tallest woman at 7 feet 7 inches tall. Tallest on record is 8 feet 11 inches

26. http://www.youtube.com/watch?v=F9-l71vUer0

29. Feather Duster Budgie(parakeet) This is a genetic mutation called Feather Duster that is exhibited in some parrots. Spontaneous mutation on a recessive gene Ultra-rare Die within first year Struggle with mobility and perching

30. White tiger with down syndrome • Parents were brother and sister • Greed of the breeding industry • This tigers siblings all died except for one • Repeated deaths • Neither could be sold due to deformities