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 Velazquez – series

of dwarf paintings in the 1600s

History Cont.

• Exhibited in circus shows, especially in the late 1800s – mid 1900s

• Came to be known

as “circus freaks”

The Cause – Missense Mutation

• Achondroplasia (ACH) is caused by a missense mutation in FGFR3 (fibroblast growth factor receptor 3) on chromosome 4p 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 cDNA)

• 3% have a cytosine 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 FGFR3 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 vast majority of FGFR3 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 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 muta-tions or difficulty of the diseased to reproduce

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 ~ 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 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 puncture

- Small pelvic size

- Anesthesia risks

- Assortive mating

- Gene lethality

Similar Dwarfing Diseases

• ACH is the most common of ~200 kinds

• Thanatophoric dysplasia (TD)

• Hypochondroplasia

• FGFR3 regulation is linked to all kinds

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 if a parent is diseased

• At least X-ray analysis, at most RFLP – restriction enzyme SfcI

• May diagnose prenatal embryos

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 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 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 for the Detection of the Common Mutation in the FGFR3 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 FGFR3 1138 a (G380R) mutation in two sibs sharing a 4p 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 J. bull, et al. “Health Supervision for Children with Achondroplasia.” Pediatrics. Sep. 2005. Vol116, 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, 2nd 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.usuf2.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://phpbb-host.com/phpbb/viewtopic.php?p=5395&mforum=thenile&