1. Genomics and Me: Living with a Cystic Fibrosis Family S. Carlson BL 3300 06 December 2002

2. What is Cystic Fibrosis? Also called CF Autosomal recessive inherited disorder Affects respiratory, digestive, and reproductive systems 1 in ~2000 births Most common lethal genetic disease in Caucasions –1 in ~200 births

3. Graphic Source: Welsh, Michael J., and Smith, Alan E. Scientific American, December 1995 http://www.people.virginia.edu/~rj h9u/cfsciam.htmc http://www.people.virginia.edu/~rj h9u/cfsciam.htmc

4. Gene discovered in 1989 Dr. Lap-Chee Tsui Dr. Jack Riordan Chromosome 7 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Graphic Source: NCBI The Human Gene Map http://www.ncbi.nlm.nih.gov/cgi-bin/SCIENCE96/gene?CFTR http://www.ncbi.nlm.nih.gov/cgi-bin/SCIENCE96/gene?CFTR

5. CFTR Gene Long arm of chrom 7 Over 6000 nucleotides Spread over 27 exons Graphic Source: “CF Pictures” http://personal.nbnet.nb.ca/normap/cfpictures.htm

6. One Amino Acid Since discovery of CFTR in 1989, over 900 mutations associated with CF Most common: deletion of one phenylalanine residue at position 508 (F508) Accounts for 70% of all CF alleles worldwide Phenylalanine (f, Phe) Graphic Source: www.chemfinder.com

7. What does CFTR do? Regulates cAMP pumps –Cl - channels –Na + / Cl - equilibrium –Water balances concentration of Na + and Cl - across cell –Fluid secretion

8. Mutated CFTR In CF patients, Cl - channel regulated by CFTR is closed Decrease of Cl - secretion Increase in Na + transport in volume- absorbing epithelia due to increase in Na + channel activity Results –Thick sticky mucous in lungs Environment for bacteria to grow –CFTR pumps in liver and pancreas also affected

9. My Family Tree Graphic Source: “Facts About Cystic Fibrosis” http://www.nhlbi.nih.gov/health/public/lung/other/cf.htm#what

10. CF in My Family August 18, 1985 – Lyn Carlson born Colicky baby? Crying, no weight gain due to lack of nutrition from food Diagnosed with cystic fibrosis –65 Roses? Enzyme supplements Respiratory Therapy

11. Treatment Preventative –Postural drainage –Positive expiratory pressure (PEP) mask –Flutter valve Lung infection –Vaccines –Antibiotics Enzyme Regulation Diet Regulation

12. Complication: CFRD Cystic Fibrosis Related Diabetes (CFRD) Depressed pancreatic insulin production –Insulin injections –Additional diet regulation

13. Complication: Depression Adolescents deal with tough issues Lyn –Anorexia –Bulemia –Depression –Feeling out of control of life Symptoms aren’t published

14. Am I a Carrier? Genetic counseling The “odds” Insurance discrimination –Widespread confusion over difference between being a carrier of a genetic disease and actually having disease –Few legal safeguards to protect genetic “carriers” –Since then, legislation passed in some states –Husband to be tested

15. Hope for a Cure Gene therapy –Introduce healthy CFTR gene into CF cells –Virus (vector) introduces gene Research has established that: –Gene transfer is possible –Expression of transferred gene is possible in humans –Expression sufficient to compensate for CFTR deficiency –Ebola, influenza may be promising leads Some unanswered questions

16. Genomics and Me Behavior as a child Choice of Michigan Tech Decision to have children Decision to become a doctor

17. Lyn Carlson – Age 17 and Doing Well!

18. Questions?

19. References NCBI The Human Gene Map http://www.ncbi.nlm.nih.gov/cgi- bin/SCIENCE96/gene?CFTRhttp://www.ncbi.nlm.nih.gov/cgi- bin/SCIENCE96/gene?CFTR Welsh, Michael J., and Smith, Alan E. Scientific American, December 1995 http://www.people.virginia.edu/~rjh9u/cfsciam.htmc http://www.people.virginia.edu/~rjh9u/cfsciam.htmc Bland, Amy, Gibson, Kevin, and Mayorga, Angela. Cystic Fibrosis. http://medicine.creighton.edu/forpatients/CF/cf.html http://medicine.creighton.edu/forpatients/CF/cf.html CF Currents: At Home Edition. Winter 1994, Vol. 2, No. 1. McNeil Pharmaceutical Co., Raritan, NJ. CF Currents: At Home Edition. Fall 1997, Vol. 5, No. 3. McNeil PharmaceuticalCo., Raritan, NJ. “CF Pictures” http://personal.nbnet.nb.ca/normap/cfpictures.htm Cystic Fibrosis Central Florida Support Group. CF Informer. Nov-Dec. 2000, Vol. XIV, Orlando, FL. Cystic Fibrosis Central Florida Support Group. CF Informer. Jan-Feb 1999, Vol. X, Orlando, FL. “Facts About Cystic Fibrosis” http://www.nhlbi.nih.gov/health/public/lung/other/cf.htm#what Orenstein, David M. Cystic Fibrosis: A Guide for Patient and Family. 1997.Lippincott-Raven Publishers, Philadelphia PA. http://www.cysticfibrosis.com/ http://www.hum-molgen.de/bb/Forum7/HTML/000268.html http://www.chemfinder.com