Suppression of severe achondroplasia with developmental delay and acanthosis nigricans by the p.Thr651Pro mutation.

[achondroplasia]

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN ) is an extremely rare severe skeletal dysplasia characterized by significant developmental delay , brain structural abnormalities , hearing loss , and acanthosis nigricans . The disorder is the result of a single missense mutation at codon 650 (p .Lys 650 Met ) in the fibroblast growth factor receptor 3 gene (FGFR 3 ). We describe a child who initially presented with a mild achondroplasia or hypochondroplasia like phenotype . Molecular analysis of the FGFR 3 gene showed the common SADDAN mutation and a second novel mutation at codon 651 (p .Thr 651 Pro ). Both mutations were shown to occur on the same allele (cis ) and de novo . Transient transfection studies with FGFR 3 double mutant constructs show that the p .Thr 651 P ro mutation causes a dramatic decrease in constitutive receptor kinase activity than that observed by the p .Lys 650 Met mutation . Our data suggest that the molecular effect by the p .Thr 651 P ro is to elicit a conformational change that decreases the FGFR 3 tyrosine kinase activity , which is constitutively activated by the SADDAN mutation . Due to the inheritance of both a gain-of-function and a loss -of-function mutation , we conclude that a reduction of constitutive activation caused the milder skeletal phenotype . Although the occurrence of double mutations are expected to be rare , the presence of other FGFR 3 modifiers may be responsible for some of the clinically discrepant skeletal dysplasia cases .

Diseases
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Diseases presenting "clinically discrepant skeletal dysplasia cases" symptom

achondroplasia

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