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theory was proven incorrect, owing to the fact that the report was withdrawn based on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