Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.
Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions.
Sarkozy
Anna
A
IRCCS, San Giovanni Rotondo, Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza, Rome, Italy.
Carta
Claudio
C
Moretti
Sonia
S
Zampino
Giuseppe
G
Digilio
Maria C
MC
Pantaleoni
Francesca
F
Scioletti
Anna Paola
AP
Esposito
Giorgia
G
Cordeddu
Viviana
V
Lepri
Francesca
F
Petrangeli
Valentina
V
Dentici
Maria L
ML
Mancini
Grazia M S
GM
Selicorni
Angelo
A
Rossi
Cesare
C
Mazzanti
Laura
L
Marino
Bruno
B
Ferrero
Giovanni B
GB
Silengo
Margherita Cirillo
MC
Memo
Luigi
L
Stanzial
Franco
F
Faravelli
Francesca
F
Stuppia
Liborio
L
Puxeddu
Efisio
E
Gelb
Bruce D
BD
Dallapiccola
Bruno
B
Tartaglia
Marco
M
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005145:Face / Q000002:abnormalities; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000473:pathology; D006801:Humans; D044542:LEOPARD Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012868:Skin Abnormalities
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf