10/17/2008

Achondroplasia Natural History of Achondroplasia p
Autosomal Dominant Gene Mutation The most common hereditary form of dwarfism. Incidence rate is between 1 in 15,000 and 1 in 40 000 live births 40,000 births. It is a fully penetrant autosomal dominant disorder and the majority of cases (7580%) are the result of a new (de novo) mutation.

Achondroplasia
Affected individuals have short stature in arms and legs but not torso. Other skeletal problems include trident hands, midfacial hypoplasia, prominent forehead (frontal bossing), thoracolumbar gibbus (hunched back), true megalencephaly, and narrowing of the spaces between g p y, g p the pedicles of the vertebra. Overall survival and the average life expectancy for ACH population are decreased by 10 years. ACH individuals are at greater risk for heart problems. Bone abnormalities of the spine like narrow foramen magnum and spinal canal stenosis affect mortality at all ages but particularly in children. Most individuals have normal intelligence.

Achondroplasia
Autosomal Dominant Point mutation in FGFR3 (Fibroblast growth factor receptor 3) Gene located on Chromosome 4p16.3 OMIM: #100800 OMIM: *134934 http://www.ncbi.nlm.nih.gov /entrez/dispomim.cgi?id=10 0800

Identifying Chromosomal Location of the ACH mutation
Velinov et al. (Nature Genetics 6, 314 - 317 (1994) ) mapped the achondroplasia gene near the telomere of the short arm of chromosome 4 (4p16.3), by family linkage studies using 14 pedigrees. A positive l d score of z=3.35 with no iti lod f 3 35 ith recombinants was obtained with an intragenic marker for IDUA (Apha-L-Iduronidase) mapped earlier. Shiang et al. and by Rousseau et al. used the “Candidate Gene Approach” to specifically identify the gene involved.
Look in the sequences in the region for a gene which could biologically make sense as the cause of Achondroplasia

Growth Factor
A naturally occurring protein capable of stimulating cellular proliferation and cellular differentiation. Growth factors are important for regulating a p g g variety of cellular processes by promoting cell differentiation and maturation. Growth factors act as signaling molecules between cells by binding to specific receptors on the surface of their target cells.

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differentiation. motility.4-kb cDNA of the FGFR3 gene contains an open reading frame of 2520 nucleotides and consists of 19 exons and 18 introns. What is a Fibroblast? A type of cell that synthesizes and maintains the extracellular matrix of animal tissues. or a toxin. Transmembrane Domain of a receptor usually has hydrophobic amino acid residues There are Four Fibroblast Growth Factor Receptors The FGF receptors bind to members of the fibroblast growth factor family of proteins. a hormone.10/17/2008 Growth Factor Receptors Receptors are protein molecules embedded in either the plasma membrane or cytoplasm of a cell. resulting in cellular and developmental changes. FGF Receptors have an extracellular. a pharmaceutical drug." and may be a peptide (such as a neurotransmitter). the receptors dimerize and phosphorylate themselves. The most common cells of connective tissue in animals. and angiogenesis in embryonic development. Growth factors are proteins which attach to cell receptors. Four different genes are currently known to encode distinct high-affinity FGF receptors. a cellular response is initiated. and plays a critical role in wound healing. The 4. A molecule which binds to a receptor is called a "ligand. introns There are at least 18 Fibroblast Growth Factors (FGF) The FGFs regulate cell proliferation. The dimers trigger phosphorylation (P) of downstream target proteins. to which a mobile signaling (or "signal") molecule may attach. eliciting a response from the cell. This response varies depending upon the cell p p g p type. and the growth factor type. Growth Factor Receptors have Growth Factors as their ligands. When this happens. When the GF binds the receptor. binding domain with three immunoglobulin-like domains. Provides a structural y . framework for many tissues. FGF growth factors bind to their FGF receptors in association with heparan sulphate proteoglycan (HSPG). Used in cell culture extensively. and an intracellular domain with tyrosine kinase activity. 2 . the receptor type. a single helix domain that crosses the cell’s membrane.

Several diseases other than skeletal dysplasias are also associated with somatic mutations in FGFR3. A mother and daughter were reported with a new heterozygous double mutation at the same codon 380. The mutation rate is estimated to be 0.000014 per gamete per generation. which is in the transmembrane domain of FGFR-3. Nucleotide 1138 of the FGFR3 gene is considered as the most sensitive point for germline mutation in the entire human genome. The mutation is either a . Tyrosine phosphorylation is not as common as other types of amino acid phosphorylation and can be studied with specific antibodies. 1994 Cell 78(2):335-42. a G-A transition or a G-C transversion on chromosome 4.10/17/2008 Phosphorylation Protein kinases catalyze phosphorylation. 150 of 154 unrelated achondroplasts had the Gp A transition and only three had a G-C transversion at nucleotide 1138 of the FGFR3 gene. What is the Achondroplasia Mutation? The mutation occurs in nucleotide position 1136 of the cDNA. and phosphatases reverse the process. The mutation is associated with an increased paternal age at the time of conception. entire nature. Seborrheic keratoses (skin growths) Epidermal nevi (freckles) Urothelial carcinomas (cancer of skin lining urethra) RFLP Mapping can diagnose the two different mutations Fragment sizes: 57 bp 107 bp AGC TAC CGG GTG Fragment size 164 b F t i bp AGC TAC GGG GTG Normal Allele G to C transversion Msp I Fragment sizes 55 bp 109 bp AGC TAC AGG GTG G to A Transition Sfc I 3 . These patients displayed a milder phenotype than the one encountered during achondroplasia Shiang et al. Both mutations lead to the same Amino Acid substitution Reverse Transcriptase PCR product was sequenced from heterozygous and homozygous ACH individuals revealed a point mutation within this region in the ACH individuals. Adding a phosphoryl group can change a nonpolar hydrophobic protein into a polar. Both mutations result in the substitution of an arginine residue f a glycine at position 360 of th mature id for l i t iti f the t protein. which substituted a lysine instead of the usual arginine. It has been demonstrated that the mutated allele is always from a paternal origin origin. Increased Paternal Age is Associated with this Mutation 80% of Achondroplasia occurs with no family history. Each phosphorylation reaction and its reverse requires ATP to power it. very hydrophilic molecule – in essence changing its essence.

if digested. Homozygous achondroplasia. FGFR3 is detected in resting but not growing (hypertrophic) cartilage. However. Endochondrial Ossification: Conversion of Hyaline Cartilage to Bone Calcified cartilage forms Osteoblasts Chondroblasts http://en.informatics. http://www. During endochondral ossification.org/greenbook/figures/figure8-1H.wikipedia. Joint Bone Spine 75 (2008) 125-130 Mutant Achondroplasia Mice have Skeletal Defects Homozygous Achondroplasia The presence of two alleles for achondroplasia causes a serious skeletal disorder that leads to early death from breathing failure due to constriction by a tiny chest cage and neurological problems from hydrocephalus.10/17/2008 RFLP of PCR Product PCR products of 164 BP were amplified and electrophoresed on a 6% nondenaturing polyacrylamide gel. although fatal. Achondroplasia and thanatophoric dwarfism are due to different mutations in the FGFR 3 gene. the G+A transition mutation creates an Sfc l site that.org/wiki/Image:Bone_growth. Similarities were noticed between homozygous achondroplasia and a fatal condition of newborns called thanatophoric dwarfism. the highest level of FGFR3 mRNAs is in the prebone cartilage rudiments of all bones bones. results in fragments of 55 and 109 bp.shtml 4 . has led to insights into other medical conditions. There are no Sfc l sites in the normal sequence in the FGF-DT PCR product.jax.png Richette et al. Role of FGFR3 in Development Outside of the developing central nervous system.

http://www. TD = thanatophoric dysplasia.10/17/2008 Other FGFR 3 Mutations Associated with Skeletal Defects Dwarf Horses and Dogs Genetics of these animals is not due to the same mutation in FGFR 3 analagous gene. severely limiting bone growth. The result is a mouse with excessively long bones and elongated vertebrae. 1998 Cells and Materials. The mutation increases the activity of FGFR3.cellmigration.png Gain of Function Mutations New or enhanced activity of a protein Loss of function is more common mutation Can C you thi k of another Human mutation think f th H t ti which could lead to a gain of new protein function? Knockout Mice with excessively long bones. 1996 Cell. 84. Achon = achondroplasia. 911–921 5 . long tails Deng et al. vertebrae resulting in a long tail tail. Hypochon = hypochondroplasia.org/resource/komouse/images/mousefig1. Mutations of FGF3R confer a "gain of function". The negative regulation of bone formation is lost. Craniosyn = craniosynostosis. 8: 83-87 Knockout Mice for Achondroplasia revealed New Insights The knock-out mouse model is missing the FGFR 3 receptor. Horton et al. It is proposed that the normal function of FGFR3 is to slow down the formation of bone by inhibiting the proliferation of chondrocytes. Vol. the cells that produce cartilage. elongated vertebrae.

Joint Bone Spine 75 (2008) 125-130 6 . but more recently. 79(5): 935–941. C-type natriuretic peptide (CNP) Overexpression of CNP in mutant mice chondrocytes rescues achondroplasia through a MAPK-dependent pathway Human growth hormone Body disproportion reported. more favorable and significant increases in height have been obtained over an 18-24g month period Future Therapies Counteract the overactive FGFR3 effects on endochondral bone formation. Misdiagnosis can lead to inaccurate prenatal counseling. Diagnosis of achondroplasia is usually first suspected late in gestation on the basis of longbone foreshortening incidentally discovered by ultrasonography. Current Medical Treatments for Achondroplasia Surgical limb-lengthening procedures Complications earlier. EM Am J Hum Genet. Genetic confirmation can be performed with chorionic villi sampling or amniocentesis. EM Am J Hum Genet. Joint Bone Spine 75 (2008) 125-130 Prenatal Diagnosis and Genetic Counseling Some obstetric risk for mother and child Fetal diagnosis of achondroplasia is made with certainty when one or both parents have condition.10/17/2008 CATSHL Syndrome resembles Knockout Mice for FGFR 3 Autosomal Dominant in CATSHL Pedigree Toydemir. Toydemir. 2006 November. Joint Bone Spine 75 (2008) 125-130 Selective inhibition of the FGFR3 tyrosine kinase. but more recently studies show improved height without adverse effect on trunk-leg disproportion Richette et al.with some risk to fetus. Recently a noninvasive maternal blood test has been developed. Richette et al. Disproportionately short limbs are seen in a heterogeneous group of conditions. 79(5): 935–941. Drugs like imatinib used in cancer chemotherapy blocking antibodies in order to interfere with binding of FGF ligands to FGFR3 Richette et al. 2006 November.

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