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
Validation

Diseases presenting "growth factor receptor" symptom

achondroplasia

aromatase deficiency

cholangiocarcinoma

dedifferentiated liposarcoma

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

kallmann syndrome

lymphangioleiomyomatosis

oral submucous fibrosis

proteus syndrome

severe combined immunodeficiency

wiskott-aldrich syndrome

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