Inherited Human Disease

Somatic mutations - single mutational event may affect large number of cells if mutation occurred early in development

Germ cell mutations - hereditary

Defects may be caused by single gene (cystic fibrosis, Duchenne muscular dystrophy) or multiple genes (spina bifida - more than 1 gene, Down syndrome - extra chromosome)

Cystic fibrosis

Fibrous scar tissue builds up in lungs, patients eventually die of respiratory failure

CFTR protein - cystic fibrosis gene product (cystic fibrosis transporter)

Found in cell membrane, acts as channel for chloride ions. Has 12 membrane-spanning segments with central control module in the center

If protein is phosphorylated (has phosphate attached) channel is open but is closed if dephosphorylated

Gene located on long arm of chromosome 7. Gene was cloned and sequenced

250,000 bp with 24 exons that code for protein of 1,480 a.a.

(Are all 250,000 bp coding? No. If so, protein would have over 83,000 a.a.)

Only 2% of the gene is coding (exons)

70% of cystic fibrosis patients in the U.S. have defect of single a.a. - missing a.a. #508 - so that protein is improperly folded and therefore nonfunctional

A+ = normal CFTR gene; is dominant

ACFTR = mutant CFTR gene; is recessive

A is an autosomal gene - located on an autosome

A person who is A+/A+ is normal (does not have cystic fibrosis)

A person who is A+/ACFTR is a carrier (does not have cystic fibrosis but may pass the mutant gene onto their offspring). Carriers are somewhat resistant to dehydration due to diarrhea from diseases such as cholera and dysentery.

A person who is ACFTR/ACFTR has cystic fibrosis

Embryonic testing: A man and a woman who were both carriers (A+/ACFTR) wanted to have a child. So they had her egg cells fertilized in vitro by his sperm cells. The resulting fertilized eggs were then tested by PCR to determine if they contained the normal or mutant genes. A fertilized egg that was A+/A+ was chosen for implantation into the woman's uterus.

Duchenne muscular dystrophy

Deterioration of muscle tissue

Sex-linked - gene is located on the X chromosome

dmd gene - produces dystrophin protein which is thought to play role in attachment of muscle fibrils; is the largest human gene

Over 2 million bp with 75 exons that code for protein of 4,000 a.a. Less than 1% of the gene is coding (exons)

Mutation may be single base change or huge deletion

Monoamine oxidase is now used as the example of a sex-linked mutation.

Genetic counseling

Can do fetal testing (amniocentesis) or adult testing

If gene has been identified, can actually look at gene of fetus at risk

Gene therapy

Alter genes in body; somatic changes so not heritable

Uses attenuated viruses (retrovirus or adenovirus) as vector for good gene

Normal cystic fibrosis gene put in adenovirus b/c virus normally attacks lining of lungs. Used in a nasal spray. Good gene is incorporated into lung cells.

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SIUC / College of Science / Microbiology / courses / MICR302

URL: http://www.micro.siu.edu/micro302/disease.html
Last updated: 9-April-98 / laa