Achondroplasia Molecular Basis of the Disease

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Achondroplasia is characterized by short stature, predominantly with shortening of the upper arms and thighs, more normal length of the forearms, lower legs, and torso, and an average adult height of approximately 4 feet. Other features include prominent forehead, flattened nasal bridge, lordosis, spinal stenosis, tibial bowing, and obstructive apnea. Achondroplasia results from a dominant gain-of-function mutation in the FGFR3 gene. One very common mutation, a G^-A transition at nucleotide 1138 that leads to the substitution of glycine 380 by arginine (G380R), accounts for approximately 97% to 98% of cases. One less common mutation, also G380R (nucleotide 1138 G^C), accounts for a further 1% to 2% of cases. The remainder are very rare mutations, G375C and G346E. When both partners of a couple have achondroplasia, there is a 1 in 4 chance of homozygous achondroplasia for each pregnancy. This is a much more severe disease that, like thanatophoric dysplasia, also affects the ribs and is lethal. Approximately 80% of cases of achondroplasia are the result of a new mutation, making nucleotide 1138 of the FGFR3 gene the most frequently mutated nucleotide known in humans. Current data support the observation that all cases of de novo mutation occur in the paternally inherited allele of FGFR3, and the incidence of achondroplasia correlates with advanced (>35 years) paternal age.

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