Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.
The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. X-linked thrombocytopenia (XLT) is an allelic variant of WAS which presents with a milder phenotype, generally limited to thrombocytopenia. WAS and XLT are caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene which encodes a 502-amino acid protein, named WASP. WASP is thought to play a role in actin cytoskeleton organization and cell signaling. Here, we report the identification of 141 unique mutations, 71 not previously reported, from 227 WAS/XLT families with a total of 262 affected members. When possible we studied the effects of these mutations on transcription, RNA splicing, and protein expression. By analyzing a large number of patients with WAS/XLT at the molecular level we identified 5 mutational hotspots in the WASP gene and have been able to establish a strong association between genotype and phenotype.
Department of Pediatrics, University of Washington, Seattle, WA 98109, USA.
Yinzhu
Y
Jin
Cinzia
C
Mazza
Jacinda R
JR
Christie
Silvia
S
Giliani
Maurilia
M
Fiorini
Patrizia
P
Mella
Francesca
F
Gandellini
Donn M
DM
Stewart
Qili
Q
Zhu
David L
DL
Nelson
Luigi D
LD
Notarangelo
Hans D
HD
Ochs
D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D014176:Protein Biosynthesis / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D014158:Transcription, Genetic / Q000235:genetics*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics*; D051316:Wiskott-Aldrich Syndrome Protein
D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein