Successful renal transplantation in a patient with a Wiskott-Aldrich syndrome protein (WASP) gene mutation

The recently-identified Wiskott-Aldrich syndrome protein gene (WASP) is responsible for the Wiskott-Aldrich X-linked immunodeficiency as well as for isolated X-linked thrombocytopenia (XLT). To characterize the regulatory sequences of the WASP gene, we have isolated, sequenced and functionally analyzed a 1.6-Kb DNA fragment upstream of the WASP coding sequence. Transfection experiments showed that this fragment is capable of directing efficient expression of the reporter chloramphenicol acetyltransferase (CAT) gene in all human hematopoietic cell lines tested. Progressive 5′ deletions showed that the minimal sequence required for hematopoietic-specific expression consists of 137 bp upstream of the transcription start site. This contains potential binding sites for several hematopoietic transcription factors and, in particular, two Ets-1 consensus that proved able to specifically bind to proteins present in nuclear extracts of Jurkat cells. Overexpression of Ets-1 in HeLa resulted in transactivation of the CAT reporter gene under the control of WASP regulatory sequences. Disruption of the Ets-binding sequences by side-directed mutagenesis abolished CAT expression in Jurkat cells, indicating that transcription factors of the Ets family play a key role in the control of WASP transcription.

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A novel WASP gene mutation in a Chinese boy with Wiskott–Aldrich syndrome

International Journal of Hematology ◽

10.1007/s12185-010-0644-3 ◽

2010 ◽

Vol 92 (2) ◽

pp. 271-275 ◽

Cited By ~ 1

Author(s):

Hongtao Yu ◽

Ting Liu ◽

Wentong Meng ◽

Li Hou

Keyword(s):

Gene Mutation ◽

Wiskott Aldrich Syndrome ◽

Wasp Gene

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A Novel WASP Gene Mutation in a Chinese Boy with Wiskott–Aldrich Syndrome

Indian Journal of Hematology and Blood Transfusion ◽

10.1007/s12288-014-0403-3 ◽

2014 ◽

Vol 30 (S1) ◽

pp. 353-355

Author(s):

Hui Wu ◽

Cheng Hu ◽

Dan Dang ◽

Ying-Jie Guo

Keyword(s):

Gene Mutation ◽

Wiskott Aldrich Syndrome ◽

Wasp Gene

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The Mouse Homolog of the Wiskott–Aldrich Syndrome Protein (WASP) Gene Is Highly Conserved and Maps near the Scurfy (sf) Mutation on the X Chromosome

Genomics ◽

10.1006/geno.1995.9979 ◽

1995 ◽

Vol 29 (2) ◽

pp. 471-477 ◽

Cited By ~ 32

Author(s):

JONATHAN M.J. DERRY ◽

PHILIPP WIEDEMANN ◽

PATRICK BLAIR ◽

YUKER WANG ◽

JULIE A. KERNS ◽

...

Keyword(s):

X Chromosome ◽

Mouse Homolog ◽

Wiskott Aldrich Syndrome ◽

Wasp Gene ◽

Syndrome Protein

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A 5′ Regulatory Sequence Containing Two Ets Motifs Controls the Expression of the Wiskott-Aldrich Syndrome Protein (WASP) Gene in Human Hematopoietic Cells

Blood ◽

10.1182/blood.v91.12.4554 ◽

1998 ◽

Vol 91 (12) ◽

pp. 4554-4560 ◽

Cited By ~ 28

Author(s):

A. Petrella ◽

I. Doti ◽

V. Agosti ◽

P. Carandente Giarrusso ◽

D. Vitale ◽

...

Keyword(s):

Transcription Factors ◽

Jurkat Cells ◽

Regulatory Sequence ◽

Regulatory Sequences ◽

Specific Expression ◽

Wiskott Aldrich Syndrome ◽

Nuclear Extracts ◽

Ets Family ◽

Wasp Gene ◽

Syndrome Protein

Abstract The recently-identified Wiskott-Aldrich syndrome protein gene (WASP) is responsible for the Wiskott-Aldrich X-linked immunodeficiency as well as for isolated X-linked thrombocytopenia (XLT). To characterize the regulatory sequences of the WASP gene, we have isolated, sequenced and functionally analyzed a 1.6-Kb DNA fragment upstream of the WASP coding sequence. Transfection experiments showed that this fragment is capable of directing efficient expression of the reporter chloramphenicol acetyltransferase (CAT) gene in all human hematopoietic cell lines tested. Progressive 5′ deletions showed that the minimal sequence required for hematopoietic-specific expression consists of 137 bp upstream of the transcription start site. This contains potential binding sites for several hematopoietic transcription factors and, in particular, two Ets-1 consensus that proved able to specifically bind to proteins present in nuclear extracts of Jurkat cells. Overexpression of Ets-1 in HeLa resulted in transactivation of the CAT reporter gene under the control of WASP regulatory sequences. Disruption of the Ets-binding sequences by side-directed mutagenesis abolished CAT expression in Jurkat cells, indicating that transcription factors of the Ets family play a key role in the control of WASP transcription.

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Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation

Blood ◽

10.1182/blood-2003-05-1592 ◽

2004 ◽

Vol 104 (13) ◽

pp. 4010-4019 ◽

Cited By ~ 196

Author(s):

Yinzhu Jin ◽

Cinzia Mazza ◽

Jacinda R. Christie ◽

Silvia Giliani ◽

Maurilia Fiorini ◽

...

Keyword(s):

Rna Splicing ◽

Strong Association ◽

Wiskott Aldrich Syndrome ◽

Cytoskeleton Organization ◽

Number Of Patients ◽

Increased Risk ◽

Mutational Hotspots ◽

Actin Cytoskeleton Organization ◽

Wasp Gene ◽

Syndrome Protein

Abstract 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. (Blood. 2004;104:4010-4019)

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Mutational screening of WASP gene in patients with Wiskott-Aldrich syndrome

Vietnam Journal of Biotechnology ◽

10.15625/1811-4989/14671 ◽

2021 ◽

Vol 19 (1) ◽

pp. 61-68

Author(s):

Luong Thi Lan Anh ◽

Nguyen Thanh Hoa ◽

Nguyen Hai Ha ◽

Dang Ton Nguyen

Keyword(s):

Viral Infections ◽

Clinical Symptoms ◽

Data Set ◽

Wiskott Aldrich Syndrome ◽

Immunodeficiency Disorder ◽

Increased Risk ◽

Wasp Gene ◽

Families With Children ◽

Syndrome Protein ◽

Flanking Regions

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder characterized by thrombocytopenia and small-sized platelets, eczema, recurrent bacterial and viral infections, higher incidence of autoimmunity and an increased risk of malignancies. WAS occurs due to the mutation or loss of Wiskott-Aldrich Syndrome Protein (WASP) gene located on Xp11.22 – p11.23 of the short arm of the X chromosome. The absence of functional WASP leads to severe clinical symptoms that results in the deaths of patients if they are not diagnosed and treated early. The objective of the study was to identify mutations in the WASP gene of families with children diagnosed with WAS.The whole coding sequence and the intron-exon flanking regions of the WASP were sequenced by Sanger method. Two cases of children who has WAS were found tocarrymutations in the WASP gene. A c.702insAC mutation leadeda frameshift at position of codon 236 and terminated the protein at the position of codon 262 was identified in patient WA007 and a c.91G>A mutation that transformed glutamic acid to lysineat codon 31 was determined in patient WA010.This study provides a data set and screening of mutations in theWASP gene inVietnamese patientsto further identify the genetic causes and contribute to the clinical management and genetic counseling for the affected families.

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Mutation Spectrum in Patients with Wiskott-Aldrich Syndrome and X-linked Thrombocytopenia: Identification of Twelve Different Mutations in the WASP Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650318 ◽

1996 ◽

Vol 75 (04) ◽

pp. 546-550 ◽

Cited By ~ 21

Author(s):

Marianne Schwartz ◽

Albert Békássy ◽

Mikael Donnér ◽

Thomas Hertel ◽

Stefan Hreidarson ◽

...

Keyword(s):

Base Pair ◽

Hot Spot ◽

Missense Mutations ◽

Nucleotide Substitutions ◽

Exon 2 ◽

Wiskott Aldrich Syndrome ◽

Base Pair Deletion ◽

Reliable Diagnosis ◽

Wasp Gene ◽

Detection Of Mutations

SummaryTwelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

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