Genetics

1. Genetics Yu Lu Department of Rheumatology Ren Ji Hospital

2. Achondroplasia Achondroplasia vs. Chondroplasia (软骨发育不全)　（软骨生成） a- chondro- Plasia

3. What is achondroplasia? • Achondroplasia is a genetic disorder of bone growth that is evident at birth. It affects about one in every 25,000 births and it occurs in all races and in both sexes. Its depiction in ancient Egyptian art makes it one of the oldest recorded birth defects. • The word achondroplasia is derived from Greek and means "without cartilage formation," although individuals with achondroplasia do have cartilage. During fetal development and childhood, cartilage normally develops into bone, except in a few places, such as the nose and ears. In individuals with achondroplasia, something goes wrong during this process, especially in the long bones (such as those of the upper arms and thighs). The rate at which cartilage cells in the growth plates of the long bones turn into bone is slow, leading to short bones and reduced height.

4. What does a person with achondroplasia look like? • A child with achondroplasia has a relatively normal torso and short arms and legs. The upper arms and thighs are more shortened than the forearms and lower legs. Generally, the head is large, the forehead is prominent and the nose is flat at the bridge. Sometimes, the large head size reflects hydrocephalus (excess fluid in the brain), and require surgery. • Hands are short with stubby fingers. There is a separation between the middle and ring fingers (trident hand). Most individuals with achondroplasia eventually reach an adult height of about 4 feet.

5. What causes achondroplasia?(1) • Achondroplasia is caused by an abnormal gene located on one of the chromosome 4 pair (humans have 23 pairs of chromosomes). • In some cases, a child inherits achondroplasia from a parent who also has the condition. If one parent has the condition and the other does not, there is a 50 percent chance that their child will be affected. If both parents have achondroplasia, there is a 50 percent chance that the child will inherit the condition, a 25 percent chance that the child will not have it, and a 25 percent chance that the child will inherit one abnormal gene from each parent and have severe skeletal abnormalities that lead to early death. A child who does not inherit the gene will be completely free of the condition, and cannot pass it on to his or her own children.

6. What causes achondroplasia?(2) • In more than 80 percent of cases, however, achondroplasia is not inherited but results from a new mutation (change) that occurred in the egg or sperm cell that formed the embryo. The parents of children with achondroplasia resulting from new mutations are usually normal-sized.Typically, these parents have no other children with achondroplasia, and the chances of their having a second affected child are extremely small. Geneticists have observed that older-than-average fathers (age 40 and older) are more likely to have children with achondroplasia and certain other autosomal dominant conditions caused by new mutations. Individuals with achondroplasia resulting from new mutations transmit the disorder to their children as described above.

7. Can achondroplasia be diagnosed before birth? • In 1994, researchers identified the gene that causes achondroplasia. This discovery allowed the development of highly accurate prenatal tests that can diagnose or rule out achondroplasia. These tests can be offered when both expectant parents have achondroplasia. In such cases, the baby has a one- in-four chance of inheriting an abnormal gene from each parent and developing a fatal form of achondroplasia. After birth, it generally is diagnosed by physical examination and X-rays.

8. How is achondroplasia treated? • There currently is no way to normalize skeletal development of children with the disorder……

9. Can achondroplasia be prevented? • There is no way to prevent the majority of cases of achondroplasia, since these births result from totally unexpected gene mutations in unaffected parents. Genetic counseling can help affected adults make informed decisions about family planning.

10. What research is being done on achondroplasia? • As noted above, scientists have identified the gene, and the exact mutation (change) in the gene, that causes achondroplasia. The gene is one of a family of genes that makes proteins called fibroblast growth factor receptors. Scientists have recently linked these genes with several skeletal disorders.The fibroblast growth factor receptor gene dictates the production of a protein that is located on the surface of cells of different tissue types, including cartilage. The protein normally responds to signals from chemicals called growth factors which stimulate cell growth and maturation.Now scientists are investigating how the faulty protein actually causes the features of achondroplasia. This eventually may lead to improved treatment for this disorder, as well as improved understanding and treatment of other skeletal disorders caused by this family of genes. March of Dimes scientists and other researchers also are working to identify the genes that cause some of the other more than 100 forms of disproportionate short structure.

11. Additional Sources of Information • For further information on support groups for individuals with achondroplasia or other forms of growth deficiency, contact:Little People of America (LPA)P.O. Box 745Lubbock, TX 79408888-LPA-2001Human Growth Foundation997 Glen Cove Ave.Glen Head, NY 11545800-451-6434The Magic Foundation for Children's Growth and Related Adult Disorders1327 N. Harlem Ave.Oak Park, IL 60302708-383-0808

12. Twins

14. Twin Operation! “WOW! Two Iranian Siamese Twins are to be seprataed! They are Iranian, and the word Siamese is not an ethnical modifier of the Twins, but a description of the fact that they are connected at the head! Jenna and Barbara sure are lucky they were not stapled together in the womb: the surgery will last 48 hours for these Iranian women: may the operation go smoothly. ”

16. 9/11/2001 • Jenna and Barbara were wisked away to a secret location since September 11th. The Secret service quickly protected them due to the bombing of the World Trade Center and The Pentagon. TheFirstTwins.com is saddened by the destruction on 9/11/2001.

17. Who is Who? • Jenna is on the left, Barbara is on the right. • Barbara is on the left, Jenna is on the right. • Holy body snatchers, those ain't them!

18. Discovery of the Double Helix

19. Scientists from several laboratories quickly realized that unraveling the three dimensional structure of DNA was the key to understanding its function. • Using wire models, chemical knowledge, and X-ray crystallography, Watsonand Crick established the Double Helix structure of DNA.  Two antiparallel sugar phosphate chains wind around the outside of the molecule; the nitrogenous bases project into the interior, where they hydrogen-bond in pairs, A with T and G with C.

20. DNA replication • Meselson and Stahl demonstrated that DNA replication is semiconservative, confirming Watson and Crick's hunch that the parent molecule unwinds and each strand then serves as a template for the synthesis of a new half-molecule according to base-pairing rules. • Some impressive complexities underlie the apparent simplicity of DNA replication, with more than a dozen extremely rapid and amazingly accurate process. （underlie/underline/underlay） • After binding of specific proteins, the initiation of replication begins at special sites called origins of replication, forming Y-shaped replication forks……

21. DNA repair • DNA molecules require continuous monitoring and repair because of ongoing assault by mutagens • DNA repair enzymes restore the integrity of the molecule by processes such as excision repair, which take advantage of base paring principles.

22. Alternative forms of DNA

23. Polymerase Chain Reaction (PCR) • Polymerase chain reaction (PCR), is a common method of creating copies of specific fragments of DNA. PCR rapidly amplifies a single DNA molecule into many billions of molecules. • In one application of the technology, small samples of DNA, such as those found in a strand of hair at a crime scene, can produce sufficient copies to carry out forensic tests.