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 "hearing loss" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

benign recurrent intrahepatic cholestasis

canavan disease

cohen syndrome

congenital toxoplasmosis

dentinogenesis imperfecta

fabry disease

familial mediterranean fever

heparin-induced thrombocytopenia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

neonatal adrenoleukodystrophy

pendred syndrome

von hippel-lindau disease

wolf-hirschhorn syndrome

This symptom has already been validated