Heston Allred

BIO 340

Steele

Achondroplasia

Evidence suggests that achondroplasia is caused by genetic mutation “in the

fibroblast growth factor receptor-3 gene which is located at 4p16.3. It is an autosomal

dominant disorder showing complete penetrance with the majority of mutations being

expressed sporadically in terms of phenotype. This is caused by de novo mutations in 7/8

cases.

“Evidence advanced by Strong and Eng et al. originally suggested that

Achondroplasia was caused by “abnormalites with the type II collagen gene in

Achondroplasia” or more specifically by DNA insertion into the gene. However this

theory was proven incorrect, owing to the fact that the report was withdrawn based on

figures in the study which, “were improperly assembled and therefore [could not] be used

to support the conclusions of the article” and because defects were found in the COL2A1

gene in SEDC, a disease whose characteristics fit the gene function more appropriately.

Eventually through, “linkage studies using DNA markers, Velinov et al.

(1994) and Le Merrer et al. (1994) mapped the gene for achondroplasia and

hypochondroplasia to the distal area of the short arm of chromosome 4 (4p16.3).” Then,

Francomano et al. (1994)… mapped the ACH gene to 4p16.3.” This was done using 18

multigenerational families with achondroplasia and through analysis of a genetically

recombinant family the ACH locus was determined to be in the, “2.5-Mb region between

D4S43 and the telomere” on chromosome 4.

Once the relative location was determined for the ACH gene, Shing et al. and

Rousseau et al. set out to determine which gene in the region had the mutation or

mutations causing the disease to be expressed phenotypically, with both conducting their

research in 1994. Eventually, “Mutations in the gene for fibroblast growth factor

receptor-3 (134934) were identified” and independently determined by both parties. In

the Shing study mutations in 15 out of 16 chromosomes showed mutations consisting of,

“a G-to-A transition at nucleotide 1138 of the cDNA.” In the case of the other

chromosome, “a G-to-C transversion at this same position” was identified. However, both

of these mutations caused a, “substitution of an arginine residue for a glycine at position

380 of the mature protein, which is in the transmembrane domain of FGFR3.” Therefore,

both mutations had the same effect on the product protein and FGFR3 is the targeted

gene. Rousseau et al. found mutations occurring in the same place as mentioned above.

According to the article they “found the G380R mutation in all cases studied: 17 sporadic

cases and 6 unrelated familial cases.”

A study in 1995 by Bellus et al. found achondroplasia caused by the same

mutations as the previously mentioned studies and in similar proportions to the Shing

study although the number of chromosomes tested was much larger in the Bellus study

(16 compared to 154) with 150 being the A to C substitution and the remaining three

being the G to C transversion. Again it was determined that mutations were causing the

same effects on the product protein, excluding only one case. The article states, “All 153

had the gly380-to-arg substitution; in one individual, an atypical case, the gly380-to-arg

substitution was missing.” Also, according to the article, “Nucleotide 1138 of the FGFR3

gene was the most mutable nucleotide in the human genome discovered at that time”

interestingly enough. Also related and of singular interest, is a case reported by

Suppeerti-Furga et al. in which, “a newborn with achondroplasia… did not carry the

mutation at nucleotide 1138 changing glycine-380 to arginine but had a mutation causing

substitution of a nearby glycine with a cysteine (134934.0003).” In 2006 Horton

determined the mutations can be considered gain of function mutations.

Furthermore, the FGFR3 gene codes “for at least 2 isoforms of the gene product”

by the mechanism of alternative splicing of two different exons thus producing proteins

with very similar function and structure. These isoforms are, “are preferentially activated

by the various fibroblast growth factors.”