Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade.
Mutations in genes coding for transducers participating in the RAS/MAPK pathway have been identified as the molecular cause underlying a group of clinically related developmental disorders with cognitive deficits of variable severity. To determine the spectrum of cognitive defects associated with dysregulation of this signal cascade, we studied the profile of cognitive abilities in patients with mutations affecting the PTPN11, SOS1, HRAS, KRAS, BRAF, RAF1, and MEK1 genes and phenotype-genotype correlations. Our findings support the observation that heterogeneity in cognitive abilities can be at least partially ascribed to the individual affected genes and type of mutation involved. While mutations affecting transducers upstream of RAS were less frequently associated with mental retardation, mutations in downstream components of the pathway were generally associated with a more severe cognitive impairment. Among patients with a heterozygous PTPN11 mutation, the T468M substitution was associated with a mean IQ significantly higher compared to that of individuals carrying the N308D change. Our study provides insights on the range of cognitive abilities in patients with gene mutations causing dysregulation of RAS signaling suggesting that the presence and severity of cognitive involvement can be predicted in part by the gene involved.
Cesarini
Laura
L
Pediatric Neurology Unit, Catholic University, Rome, Italy.
Alfieri
Paolo
P
Pantaleoni
Francesca
F
Vasta
Isabella
I
Cerutti
Marta
M
Petrangeli
Valentina
V
Mariotti
Paolo
P
Leoni
Chiara
C
Ricci
Daniela
D
Vicari
Stefano
S
Selicorni
Angelo
A
Tartaglia
Marco
M
Mercuri
Eugenio
E
Zampino
Giuseppe
G
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D020837:SOS1 Protein / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
D020837:SOS1 Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins