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Achondroplasia is defined by recurrent G380R mutations of FGFR3.

ABSTRACT: Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to three orders of magnitude higher than that previously reported for tranversions and transitions in CpG dinucleotides. To date, this represents the most mutable single nucleotide reported in the human genome. The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype.

SUBMITTER: Bellus GA

PROVIDER: S-EPMC1801129 | biostudies-other | 1995 Feb

REPOSITORIES: biostudies-other

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Achondroplasia is defined by recurrent G380R mutations of FGFR3.

Bellus G A GA Hefferon T W TW Ortiz de Luna R I RI Hecht J T JT Horton W A WA Machado M M Kaitila I I McIntosh I I Francomano C A CA

American journal of human genetics 19950201 2

Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to th ...[more]

PMID: 7847369

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Project description:BackgroundAchondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication.Methods and findingsTo achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0-3], [4-8] and [9-18] years old. Our results show unexpected results with the development of an atypical obesity with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholosterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to D22), the development of these metabolic deregulations was prevented in adult animals (between 4 and 14 weeks of age). The lean-over-fat tissues ratio was restored and glucose metabolism showed normal levels. Treating Fgfr3ach/+ mice with soluble FGFR3 during the growth period, prevented the development of these metabolic deregulations in adult animals and restored lean-over-fat tissues ratio as well as glucose metabolism in adult animals.ConclusionThis study demonstrate that achondroplasia patients develop an atypical obesity with preferential abdominal obesity not associated with classical complications. These results suggest that achondroplasia induces an uncommon metabolism of energy, directly linked to the FGFR3 mutation. These data strongly suggest that this common complication of achondroplasia should be included in the clinical management of patients. In this context, sFGFR3 proved to be a promising treatment for achondroplasia by normalizing the biology at different levels, not only restoring bone growth but also preventing the atypical visceral obesity and some metabolic deregulations.

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Achondroplasia is defined by recurrent G380R mutations of FGFR3.

Publications

Achondroplasia is defined by recurrent G380R mutations of FGFR3.

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