Achondroplasia Disease most associated with human dwarfism Occurs

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Achondroplasia • Disease most associated with human dwarfism • Occurs in 1 / 15,

Achondroplasia • Disease most associated with human dwarfism • Occurs in 1 / 15, 000 – 17, 000 people • Caused by a missense mutation

History • Obvious phenotype – documented throughout history - Ancient Egyptian artwork - Diego

History • Obvious phenotype – documented throughout history - Ancient Egyptian artwork - Diego Velazquez – series of dwarf paintings in the 1600 s

History Cont. • Exhibited in circus shows, especially in the late 1800 s –

History Cont. • Exhibited in circus shows, especially in the late 1800 s – mid 1900 s • Came to be known as “circus freaks”

The Cause – Missense Mutation • Achondroplasia (ACH) is caused by a missense mutation

The Cause – Missense Mutation • Achondroplasia (ACH) is caused by a missense mutation in FGFR 3 (fibroblast growth factor receptor 3) on chromosome 4 p in humans • This nucleotide, # 1138 in exon 10 on chromosome 4, has the highest mutation rate known • In 97% of patients, an adenine replaces the normal guanine at this position (observed in c. DNA) • 3% have a cytosine instead

Consequence • Both mutations result in the production of the amino acid arginine instead

Consequence • Both mutations result in the production of the amino acid arginine instead of glycine • This production of arginine enhances gene function and # of FGFR 3 signals released • Mitosis is promoted, but cell differentiation is depressed due to enhancement of gene function • Inhibits proliferation and terminal differentiation, resulting in reduced bone growth

Cause of Mutation • Studies show correlation with paternal age • Appears that the

Cause of Mutation • Studies show correlation with paternal age • Appears that the vast majority of FGFR 3 mutations arise as new mutations during spermatogenesis before Meiosis I • All mutations studied so far occur on the paternal chromosome

More Genetics • ACH is an autosomal dominant trait, meaning that a diseased parent

More Genetics • ACH is an autosomal dominant trait, meaning that a diseased parent has a 50% chance of passing it on (pedigree next slide) • Despite these odds, almost 90% of patients have de novo, or spontaneous, ACH • Probably due to either of two missense mutations or difficulty of the diseased to reproduce

Pedigree Analysis • Used to classify the disease as autosomal dominant • Does not

Pedigree Analysis • Used to classify the disease as autosomal dominant • Does not skip a generation, prevalent in females and males • Lethal gene – homozygous dominant individuals usually die before birth

Phenotype & Symptoms • ACH has 100% penetrance and consistent expressivity • Height of

Phenotype & Symptoms • ACH has 100% penetrance and consistent expressivity • Height of ~ 4 ft. , short extremities, slight to moderate obesity, and large head • Children have delayed motor milestones, bowing of lower legs, frequent ear infections (due to short Eustachian tube), and trouble breathing (due to airway restriction) • 2 – 5% of infants die due to symptoms

Phenotype & Symptoms Cont. • Statistics show mortality rate more than doubles the general

Phenotype & Symptoms Cont. • Statistics show mortality rate more than doubles the general population • Does not effect intelligence • Biggest challenge is overcoming social ineptitude and low self-esteem (Television show – “Little People, Big World” on TLC) - Depression is common

Reproduction Restrictions • Difficulty in reproduction due to: - Restriction of ovarian stimulation and

Reproduction Restrictions • Difficulty in reproduction due to: - Restriction of ovarian stimulation and puncture - Small pelvic size - Anesthesia risks - Assortive mating - Gene lethality

Similar Dwarfing Diseases • ACH is the most common of ~200 kinds • Thanatophoric

Similar Dwarfing Diseases • ACH is the most common of ~200 kinds • Thanatophoric dysplasia (TD) • Hypochondroplasia • FGFR 3 regulation is linked to all kinds

Other Species • ACH and other dwarfism diseases occur in other mammals, as well

Other Species • ACH and other dwarfism diseases occur in other mammals, as well • Same characteristics as in humans

Diagnosis in Humans • Easier since the phenotype is apparent at birth • Expected

Diagnosis in Humans • Easier since the phenotype is apparent at birth • Expected if a parent is diseased • At least X-ray analysis, at most RFLP – restriction enzyme Sfc. I • May diagnose prenatal embryos

Treatment • New method of adding height, called distraction osteogenesis, is being researched -

Treatment • New method of adding height, called distraction osteogenesis, is being researched - Lengthen tibia bone with very few risks - Increase of 4. 0 +/- 1. 98 centimeters • Growth hormone therapy is still under study • Gene Therapy possibility • Altered clothing, car-pedal extensions, respect from average-sized individuals, and even a support group (see next slide) all help the low self-esteem and depression that is common

Support Group Therapy • Research shows 5, 000 – 10, 000 achondroplasts in the

Support Group Therapy • Research shows 5, 000 – 10, 000 achondroplasts in the U. S. A. and 65, 000 on Earth • Support groups allow for sharing of experiences and more social interaction • Little People of America, founded by actor Billy Barty, has more than 5, 000 members • Help to lead a normal life…

References • 1) Aldegheri, Roberto. “Distraction osteogenesis for lengthening of the tibia in patients

References • 1) Aldegheri, Roberto. “Distraction osteogenesis for lengthening of the tibia in patients who have limb-length discrepancy or short stature. ” Journal of Bone and Joint Surgery. Boston: May 1999. Vol. 81, Iss. 5; pg 624. • 2) Bankowski, Leanne, and Carrie St Michel. “They couldn’t see past my size. ” Good Housekeeping. New York: Nov 1999. Vol. 229, Iss. 5; pg. 98. • 3) Henderson, Shirley, David Sillence, and John Loughlin. “Germline and somatic mosaicism in achondroplasia. ” Journal of Medical Genetics. London: Dec 2000. Vol. 37, Iss. 12; pg. 956. • 4) Horton, William A. , and Gregory P. Lunstrum. “Fibroblast Growth Factor Receptor 3 Mutations in Achondroplasia and Related Forms of Dwarfism. ” Reviews in Endocrine & Metabolic Disorders. Dec. 2002; pg. 381.

References cont. 5) Lanning, Robert W. , and Charlotte A. Brown. “An Improved Methodology

References cont. 5) Lanning, Robert W. , and Charlotte A. Brown. “An Improved Methodology for the Detection of the Common Mutation in the FGFR 3 Gene Responsible for Achondroplasia. ” Department of Pediatrics, Carolinas Medical Center, Charlotte, NC. Aug. 3, 1997. 6) Moutou, Celine, Catherine Rongieres, Karima Bettahar-Lebugle Nathalie Gardes, Christophe Philippe, and Stephane Viville. “Preimplantation genetic diagnosis for achondroplasia: genetics and gynaecological limits and difficulties. ” Human Reproduction. Mar. 200. Health Module, pg. 509. 7) Sobetzko, Diana, Suzanne Braga, Anna Rudeberg, Andrea Superti-Fura. “Achondroplasia with the FGFR 3 1138 a (G 380 R) mutation in two sibs sharing a 4 p haplotype derived from their unaffected father. ” Journal of Medical Genetics. London: Dec. 2000. Vol. 37, Iss. 12; pg 958.

References cont. 8) Trotter, Tracy L. , Judith G. Hall, G. Bradley Schaefer, Marlyn

References cont. 8) Trotter, Tracy L. , Judith G. Hall, G. Bradley Schaefer, Marlyn J. bull, et al. “Health Supervision for Children with Achondroplasia. ” Pediatrics. Sep. 2005. Vol 116, Iss. 3; pg 771. 9) Winkelman, Willem, and Rachel Buchholz. “Keep Staring: I might do a Trick!” National Geographic Kids. Washington: Nov 2004. pg. 46. 10) Young, Ian D. “Achondroplasia: A case of neglect? ” The Lancet. London: Dec. 19 – 26, 1998. Vol. 352, Iss. 9145; pg. 1950 11) Pasternak, Jack J. Human Molecular Genetics, 2 nd ed. 2005 12) http: //teratology. org/jfs/History. html Feb. 27, 2006. 13) http: //ibis-birthdefects. org/start/achondro. htm). Feb. 27, 2006.

Pictures/Diagrams 1) http: //ibis-birthdefects. org/start/achondro. htm 2) http: //bob. usuf 2. usuhs. mil/biochem/images/ped-1. gif

Pictures/Diagrams 1) http: //ibis-birthdefects. org/start/achondro. htm 2) http: //bob. usuf 2. usuhs. mil/biochem/images/ped-1. gif 3) http: //www. pathguy. com/lectures/achondroplasia. jpg 4) http: //www. mun. ca/biology/scarr/Achondroplasia. gif 5) http: //www. mun. ca/biology/scarr/Human_Achondroplasia. gif 6) http: //phpbbhost. com/phpbb/viewtopic. php? p=5395&mforum=thenile&