Original Article
Brief Report
X-Linked Wiskott–Aldrich Syndrome in a Girl
N Engl J Med 1998; 338:291-295January 29, 1998
- Article
The Wiskott–Aldrich syndrome is a life-threatening X-linked recessive disorder. Affected males present with recurrent infections, eczema, and thrombocytopenia with small platelets. The immune defect involves both humoral and cellular immunity and increases in severity with age.1
The gene involved in this disease, located on the short arm of the X chromosome in the region Xp11.22–23, was recently cloned and named the Wiskott–Aldrich syndrome protein (WASP) gene.2,3 Different mutations or deletions within the WASP gene have been described in patients with the Wiskott–Aldrich syndrome and X-linked thrombocytopenia.4 The gene is expressed in early progenitor cells as well as in differentiated cells of various hematopoietic lineages.5,6 Evidence has been presented that WASP might be involved in cytoskeleton organization and signal transduction.7
Female carriers of the disorder have no clinical signs of the gene defect because of the preferential selection of the normal, nonmutated X chromosome in their hematopoietic cells.8-10 In contrast, in skin fibroblasts and cells from the buccal mucosa of female carriers there is random inactivation of the X chromosome.8,10 There have been few reports of sporadic cases of females with a clinical disorder similar to Wiskott–Aldrich syndrome.11-13 When evaluated, the pattern of X-chromosome inactivation was found to be random, and the existence of an autosomal disorder that is clinically similar to classic Wiskott–Aldrich syndrome was postulated.
We describe an eight-year-old girl with typical features of Wiskott–Aldrich syndrome. Molecular analysis revealed a spontaneous mutation in exon 4 of the WASP gene on the paternally derived X chromosome, associated with a nonrandom pattern of inactivation of the maternally derived X chromosome. These findings show how X-linked recessive diseases may occur in females.
Case Report
In 1989 a two-month-old girl was admitted to the hospital because of stomatitis and thrombocytopenia-related petechiae. A bone marrow aspirate revealed no signs of a malignant disorder, and since all other blood values were within the normal range, a diagnosis of idiopathic immune thrombocytopenia was proposed. The patient subsequently had repeated episodes of mild bleeding that were associated with platelet counts of 5000 to 20,000 per cubic millimeter and clinical signs of immunodeficiency, manifested by repeated ear infections and several episodes of pneumonia. A varicellavirus infection had an unusually severe course, with concurrent viral keratitis and skin lesions resulting in persistent scars. The patient had eczema, which resolved over time. All blood measurements were normal with the exception of persistently low platelet counts and platelet volume (Table 1Table 1
Immunologic and Hematologic Characteristics of the Eight-Year-Old Patient.).Serum immunoglobulin measurements at eight years of age revealed elevated IgA levels and low IgM levels (Table 1). Specific antibodies to tetanus toxoid, Epstein–Barr virus nuclear antigen, and rubella virus were detected in the serum, but no antibodies against measles or mumps were found despite previous vaccination. Specific antibodies to Haemophilus influenzae type b were detected, although levels were in the low-normal range. The karyotypes of the patient and her mother were normal. Review of the family history revealed neither bleeding disorders nor immunodeficiency. The triad of thrombocytopenia with small platelets, eczema in early life, and subsequent clinical signs of immunodeficiency led to a tentative diagnosis of the Wiskott–Aldrich syndrome, and detailed molecular and immunologic diagnostic procedures were performed.
Methods
Lymphocyte phenotyping was performed by standard direct immunofluorescent techniques and evaluation with a FACStar cell sorter (Becton Dickinson, San Jose, Calif.).
Analysis of X-chromosome inactivation was performed as previously described.14 Briefly, DNA was extracted from peripheral-blood cells and cells from buccal swabs with a QIAamp tissue kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. An aliquot of DNA was digested with the methylation-sensitive enzyme HpaII (New England Biolabs, Schwalbach, Germany) and amplified by the polymerase chain reaction (PCR) at the human androgen receptor (HUMARA) gene locus with specific primers as described previously.14 The PCR products were subjected to electrophoresis on 3 percent agarose gel and stained with ethidium bromide.
For the synthesis of complementary DNA (cDNA), total cellular RNA was isolated from peripheral-blood cells with the RNeasy Total RNA kit (Qiagen), according to the manufacturer's directions. Approximately 1 μg of total RNA was used for the synthesis of cDNA (SuperScript II reverse transcriptase kit, GIBCO-BRL, Gaithersburg, Md.). The primers and PCR conditions used for the amplification of cDNA have been described previously.6 Each of the 12 exons of the WASP gene with flanking splice sites was amplified by PCR as previously described.15 The PCR products were purified and sequenced with the ABI PRISM dye terminator cycle-sequencing kit (Perkin-Elmer Cetus, Norwalk, Conn.) and analyzed with a DNA sequencer reader (model 373A, Applied Biosystems, Foster City, Calif.).
Single-strand conformation polymorphism (SSCP) analysis was performed with the Phast electrophoresis system (Pharmacia, Uppsala, Sweden). After PCR amplification the DNA samples were prepared as described previously15 and subjected to electrophoresis on 12.5 percent homogeneous Phast gel (Pharmacia) at 15°C for 150 volt-hours. The gels were stained with silver as described previously.15
Results
Immunologic and Hematologic Characteristics
Table 1 shows selected immunologic and hematologic characteristics of our patient. Serum IgA levels were consistently elevated above normal ranges, whereas serum IgM levels were lower than normal. Platelet counts and volumes were consistently low. The number of T cells positive for γ/δ T-cell receptors was increased on repeated tests over a two-year period. Quantitative analyses of other subpopulations of peripheral-blood lymphocytes were normal (Table 1). The response of T cells and cytokines to various mitogenic stimuli varied but was at some times normal (data not shown).
Analysis of X-Chromosome Inactivation in Cells from Peripheral Blood and Buccal Mucosa
We analyzed the pattern of X-chromosome inactivation in the patient by evaluating the pattern of methylation of the HUMARA gene, as previously described.14 The first exon of this gene contains a highly polymorphic trinucleotide repeat and two HpaII sites that are methylated on the inactive X chromosome but not on the active X chromosome.16
Both the patient and her mother appeared to be heterozygous at the HUMARA locus, as shown by the presence of two bands of different sizes after PCR amplification (lanes 3 and 5, respectively, in Figure 1Figure 1
Analysis of the Pattern of X-Chromosome Inactivation in the Patient and Her Parents.). In the patient, the upper DNA band represents the paternally derived allele, whereas the lower one is inherited from her mother. In the case of random inactivation of the X chromosome, as occurs in normal females, a portion of both the maternally and paternally derived X chromosomes will not be digested and both alleles will be amplified. Alternatively, if there is nonrandom inactivation of the X chromosome, the allele on the active X chromosome will be completely digested and only the other allele will be amplified.In our patient, there was skewed inactivation of the maternally derived X chromosome in both peripheral-blood cells and buccal mucosal cells (lanes 4 and 8, respectively, in Figure 1). Her healthy mother also had complete nonrandom inactivation of X chromosomes in both cell populations (lanes 6 and 10, respectively, in Figure 1). Peripheral-blood cells from the patient's maternal grandmother also showed nonrandom inactivation (data not shown). This pattern of skewed X-chromosome inactivation does not appear to be the result of cytogenetic abnormalities because both the patient and her mother had a normal karyotype (data not shown).
Identification of a Missense Mutation in the WASP Gene
Direct sequencing of the amplified products of the 12 exons of the WASP gene and flanking splice sites revealed a normal sequence throughout the patient's gene except at position 431 in exon 4, at which signals for both guanine (G) and adenine (A) were obtained. This result indicates the presence of two alleles differing at this nucleotide (Figure 2Figure 2
Sequence Analysis of Exon 4 of the WASP Gene in the Patient and Her Parents.). When the PCR product of exon 4 was cloned and 14 clones were sequenced, 6 had the wild-type G and 8 had the mutant A.Direct sequence analysis of WASP cDNA in our patient revealed only the abnormal allele (Figure 2). This finding together with the observed pattern of skewed X-chromosome inactivation indicates that the mutation resides on the active X chromosome. Since DNA analysis of both of her parents revealed a normal sequence in exon 4 (Figure 2), the mutation found in the patient must have occurred spontaneously.
To obtain further independent confirmation of these results, we performed SSCP analysis. When exon 4 of the WASP gene was amplified from DNA of a normal subject, the patient, and her parents, an altered migration pattern, indicating the presence of a mutation, was observed only in the patient's DNA (Figure 3Figure 3
SSCP Analysis of Exon 4 of the WASP Gene in the Patient, Her Parents, and a Control Subject.).Interestingly, although previous mutations identified in patients with the Wiskott–Aldrich syndrome are very heterogeneous and are present throughout the entire gene, the same change from G to A, causing the substitution of a lysine for the conserved wild-type glutamic acid at codon 133, has previously been described in three unrelated males with typical Wiskott–Aldrich syndrome.3,17 This is probably due to the fact that the mutation occurs at a cytosine–guanine (CG) dinucleotide known to be a hot spot for new mutations.
Discussion
We describe a child with classic Wiskott–Aldrich syndrome, who had thrombocytopenia with small platelets, eczema in early life, clinical immunodeficiency, and a missense mutation in the WASP gene. This case is unique because the patient is a female, and this X-linked recessive disease normally affects males.
Early in embryogenesis, one of the two X chromosomes in all somatic cells of females is inactivated.18 Although the X chromosome inactivated is picked at random, the same X chromosome is subsequently inactivated in all progeny of that cell. As a result, the normal woman is a mosaic: in some of her cells the paternally derived X chromosome is active, and in others the maternally derived X chromosome is active. If one of the two X chromosomes carries a defect that impairs cell proliferation or survival, then by default, all the cells of that lineage will be derived from precursors with the nonmutant X chromosome as the active one. In carriers of the Wiskott–Aldrich syndrome, analysis of X-chromosome inactivation in hematopoietic cells shows that only the X chromosome that does not carry the defect is active.10 Therefore, a female who is heterozygous for a mutation in the WASP gene can become symptomatic only if an additional event prevents the normal WASP allele from being active, as occurred in our patient.
Thus, this case appears to be the unfortunate result of two rare, independent genetic events. Clinical manifestations of other X-linked disorders, such as Hunter's syndrome,19 hemophilia,20 Duchenne's muscular dystrophy,21 and the Lesch–Nyhan syndrome,22 have been described in heterozygous female carriers with normal karyotypes and with a skewed pattern of X-chromosome inactivation. Together, these reports suggest that a skewed pattern of X-chromosome inactivation increases the risk of X-linked diseases in females.
The reason for the unbalanced pattern of X-chromosome inactivation in our patient is unclear. Recent evidence suggests that the inactivation process itself is genetically determined23,24 and that it can be inherited as a mendelian trait.25 In our patient, the possibility of inherited unbalanced inactivation is supported by the demonstration of a skewed pattern of X-chromosome inactivation in her mother as well as in her mother's mother. A leading candidate gene with respect to control of the process of X-chromosome inactivation is the X-inactivation–specific transcript (XIST) gene, which is expressed exclusively by the inactive X chromosome.23,24 In mice, the inactivation process is also modified by the X-controlling element (Xce) locus.23,24 Therefore, it is tempting to speculate that an alteration within one of these controlling elements may result in a skewed pattern of inactivation. A mutation in the promoter region of the XIST gene causing nonrandom X-chromosome inactivation in a family has recently been described.26
The present report should alert clinicians to the possibility of recessive X-linked diseases in females. The pattern of X-chromosome inactivation can be identified by relatively simple and rapid techniques and may add valuable information in cases in which a female patient is suspected of having an X-linked recessive disorder.
Supported by a European Community grant, by the Marie Curie Training and Mobility of Researchers program (ERB962974), and by the Fonds zur Förderung der wissenschaftlichen Forschung in Österreich.
We are indebted to Professor L.D. Notarangelo and Professor M. Eibl for helpful discussion and critical review of the manuscript, to Christian Stehlik for valuable help in sequence analysis, and to Dr. Michelle Epstein for review of the manuscript.
Source Information
From the Institute of Immunology–Vienna International Research Cooperation Center at Novartis Forschungsinstitut, University of Vienna (O.P., W.K.), and St. Anna Children's Hospital (G.R., O.A.H., J.P., H.G., W.H.) — both in Vienna, Austria.
Address reprint requests to Dr. Parolini at the Institute of Immunology–VIRCC at NFI, University of Vienna, Brunnerstr. 59, A-1235 Vienna, Austria.
- References
References
1
Remold-O'Donnell E ,Rosen FS ,Kenney DM . Defects in Wiskott-Aldrich syndrome blood cells. Blood 1996;87:2621-2631
Web of Science | Medline2
Derry JM ,Ochs HD ,Francke U . Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 1994;78:635-644[Erratum, Cell 1994;79:922a.]
CrossRef | Web of Science | Medline3
Kwan SP ,Hagemann TL ,Radtke BE ,Blaese RM ,Rosen FS . Identification of mutations in the Wiskott-Aldrich syndrome gene and characterization of a polymorphic dinucleotide repeat at DXS6940, adjacent to the disease gene. Proc Natl Acad Sci U S A 1995;92:4706-4710
CrossRef | Web of Science | Medline4
Schwarz K . WASPbase: a database of WAS- and XLT-causing mutations. Immunol Today 1996;17:496-502
CrossRef | Medline5
Stewart DM ,Treiber-Held S ,Kurman CC ,Facchetti F ,Notarangelo LD ,Nelson DL . Studies of the expression of the Wiskott-Aldrich syndrome protein. J Clin Invest 1996;97:2627-2634
CrossRef | Web of Science | Medline6
Parolini O ,Berardelli S ,Riedl E , et al. Expression of Wiskott-Aldrich syndrome protein (WASP) gene during hematopoietic differentiation. Blood 1997;90:70-75
Web of Science | Medline7
Smith CIE ,Notarangelo LD . Molecular basis for X-linked immunodeficiencies. Adv Genet 1997;35:57-115
CrossRef | Web of Science | Medline8
Fearon ER ,Kohn DB ,Winkelstein JA ,Vogelstein B ,Blaese RM . Carrier detection in the Wiskott Aldrich syndrome. Blood 1988;72:1735-1739
Web of Science | Medline9
Greer WL ,Kwong PC ,Peacocke M ,Ip P ,Rubin LA ,Siminovitch KA . X-chromosome inactivation in the Wiskott-Aldrich syndrome: a marker for detection of the carrier state and identification of cell lineages expressing the gene defect. Genomics 1989;4:60-67
CrossRef | Web of Science | Medline10
Wengler G ,Gorlin JB ,Williamson JM ,Rosen FS ,Bing DH . Nonrandom inactivation of the X chromosome in early lineage hematopoietic cells in carriers of Wiskott-Aldrich syndrome. Blood 1995;85:2471-2477
Web of Science | Medline11
Conley ME ,Wang WC ,Parolini O ,Schapiro DN ,Campana D ,Siminovitch KA . Atypical Wiskott-Aldrich syndrome in a girl. Blood 1992;80:1264-1269
Web of Science | Medline12
Russell SJ ,Nisen PD . Random X chromosome inactivation in a female with a variant of Wiskott-Aldrich syndrome. Br J Haematol 1995;90:210-212
CrossRef | Web of Science | Medline13
Kondoh T ,Hayashi K ,Matsumoto T , et al. Two sisters with clinical diagnosis of Wiskott-Aldrich syndrome: is the condition in the family autosomal recessive? Am J Med Genet 1995;60:364-369
CrossRef | Web of Science | Medline14
Wengler GS ,Parolini O ,Fiorini M , et al. A PCR-based non-radioactive X-chromosome inactivation assay for genetic counseling in X-linked primary immunodeficiencies. Life Sci 1997;61:1405-1411
CrossRef | Web of Science | Medline15
Wengler GS ,Notarangelo LD ,Berardelli S , et al. High prevalence of nonsense, frame-shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome. Blood 1995;86:3648-3654
Web of Science | Medline16
Allen RC ,Zoghbi HY ,Moseley AB ,Rosenblatt HM ,Belmont JW . Methylation of Hpall and Hhal sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992;51:1229-1239
Web of Science | Medline17
Kolluri R ,Shehabeldin A ,Peacocke M , et al. Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus. Hum Mol Genet 1995;4:1119-1126
CrossRef | Web of Science | Medline18
Lyon MF . Mechanisms and evolutionary origins of variable X-chromosome activity in mammals. Proc R Soc Lond B Biol Sci 1974;187:243-268
CrossRef | Web of Science | Medline19
Clarke JT ,Greer WL ,Strasberg PM ,Pearce RD ,Skomorowski MA ,Ray PN . Hunter disease (mucopolysaccharidosis type II) associated with unbalanced inactivation of the X chromosomes in a karyotypically normal girl. Am J Hum Genet 1991;49:289-297
Web of Science | Medline20
Nisen PD ,Waber PG . Nonrandom X chromosome DNA methylation patterns in hemophiliac females. J Clin Invest 1989;83:1400-1403
CrossRef | Web of Science | Medline21
Azofeifa J ,Voit T ,Hubner C ,Cremer M . X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum Genet 1995;96:167-176
CrossRef | Web of Science | Medline22
Aral B ,de Saint Basile G ,Al-Garawi S ,Kamoun P ,Ceballos Picot I . Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient. Hum Mutat 1996;7:52-58
CrossRef | Web of Science | Medline23
Belmont JW . Genetic control of X inactivation and processes leading to X-inactivation skewing. Am J Hum Genet 1996;58:1101-1108
Web of Science | Medline24
Lee JT ,Jaenisch R . The (epi)genetic control of mammalian X-chromosome inactivation. Curr Opin Genet Dev 1997;7:274-280
CrossRef | Web of Science | Medline25
Naumova AK ,Plenge RM ,Bird LM , et al. Heritability of X chromosome-inactivation phenotype in a large family. Am J Hum Genet 1996;58:1111-1119
Web of Science | Medline26
Plenge RM ,Hendrich BD ,Willard HF . A mutation in the XIST promoter in a family with non-random X chromosome inactivation. Am J Hum Genet 1995;57:A30-A30 abstract.
- Citing Articles (42)
Citing Articles
1
A Kloska, J Jakóbkiewicz-Banecka, A Tylki-Szymańska, B Czartoryska, G Węgrzyn. (2011) Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders. Clinical Genetics 80:5, 459-465
CrossRef2
Alain Fischer. 2010. The Immunocompromised Host. .
CrossRef3
Karen Helene Ørstavik. (2009) X chromosome inactivation in clinical practice. Human Genetics 126:3, 363-373
CrossRef4
F. Lose, D. L. Duffy, G. F. Kay, , M. A. Kedda, A. B. Spurdle. (2008) Skewed X Chromosome Inactivation and Breast and Ovarian Cancer Status: Evidence for X-Linked Modifiers of BRCA1. JNCI Journal of the National Cancer Institute 100:21, 1519-1529
CrossRef5
Simona Graziani, Gigliola Di Matteo, Luigi Benini, Silvia Di Cesare, Maria Chiriaco, Loredana Chini, Marco Chianca, Fosca De Iorio, Maria La Rocca, Roberta Iannini, Stefania Corrente, Paolo Rossi, Viviana Moschese. (2008) Identification of a Btk mutation in a dysgammaglobulinemic patient with reduced B cells: XLA diagnosis or not?. Clinical Immunology 128:3, 322-328
CrossRef6
Wen-I Lee, Chang-Yo Yang, Tang-Her Jaing, Jing-Long Huang, Yin-Hsiu Chien, Kuei-Wen Chang. (2008) Clinical Aspects and Molecular Analysis of Chinese Patients with Wiskott-Aldrich Syndrome in Taiwan. International Archives of Allergy and Immunology 145:1, 15-23
CrossRef7
G. L. Chen, J. T. Prchal. (2007) X-linked clonality testing: interpretation and limitations. Blood 110:5, 1411-1419
CrossRef8
Daniele Moratto, Silvia Giliani, Lucia D Notarangelo, Cinzia Mazza, Evelina Mazzolari, Luigi D Notarangelo. (2007) The Wiskott–Aldrich syndrome: from genotype–phenotype correlation to treatment. Expert Review of Clinical Immunology 3:5, 813-824
CrossRef9
Anupama Khare, Gad Shaulsky. (2006) First among equals: competition between genetically identical cells. Nature Reviews Genetics 7:7, 577-584
CrossRef10
Nuria Andreu, Maricruz García-Rodríguez, Victor Volpini, Cecilia Frecha, Ignacio J. Molina, Gumersindo Fontan, Cristina Fillat. (2006) A novel Wiskott-Aldrich syndrome protein (WASP) complex mutation identified in a WAS patient results in an aberrant product at the C-terminus from two transcripts with unusual polyA signals. Journal of Human Genetics 51:2, 92-97
CrossRef11
Alexis Proust, Benoit Guillet, Isabelle Pellier, Petronela Rachieru, Cyrille Hoarau, Segolene Claeyssens, Claude Leonard, Sabine Charrier, William Vainchenker, Gil Tchernia, Jean Delaunay. (2005) Recurrent V75M mutation within the Wiskott-Aldrich syndrome protein: description of a homozygous female patient. European Journal of Haematology 75:1, 54-59
CrossRef12
Francisco A. Bonilla, I. Leonard Bernstein, David A. Khan, Zuhair K. Ballas, Javier Chinen, Michael M. Frank, Lisa J. Kobrynski, Arnold I. Levinson, Bruce Mazer, Robert P. Nelson, Jordan S. Orange, John M. Routes, William T. Shearer, Ricardo U. Sorensen. (2005) Practice parameter for the diagnosis and management of primary immunodeficiency. Annals of Allergy, Asthma & Immunology 94:5, S1-S63
CrossRef13
Mary Ellen Conley, Arnon Broides, Vivian Hernandez-Trujillo, Vanessa Howard, Hirokazu Kanegane, Toshio Miyawaki, Sheila A. Shurtleff. (2005) Genetic analysis of patients with defects in early B-cell development. Immunological Reviews 203:1, 216-234
CrossRef14
Amy S. Paller. (2005) Genetic immunodeficiency disorders. Clinics in Dermatology 23:1, 68-77
CrossRef15
Alain Spatz, Christophe Borg, Jean Feunteun. (2004) X-Chromosome Genetics and Human Cancer. Nature Reviews Cancer 4:8, 617-629
CrossRef16
Hiro Matsukura, Hirokazu Kanegane, Kazushi Miya, Keisuke Ohtsubo, Akira Higuchi, Takakuni Tanizawa, Toshio Miyawaki. (2004) IgA nephropathy associated with X-linked thrombocytopenia. American Journal of Kidney Diseases 43:3, e7-e12
CrossRef17
Mindy Anderson-Cohen, Steve M Holland, Doug B Kuhns, Thomas A Fleisher, Li Ding, Sebastian Brenner, Harry L Malech, Joachim Roesler. (2003) Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation. Clinical Immunology 109:3, 308-317
CrossRef18
Kohsuke Imai, Shigeaki Nonoyama, Hans D. Ochs. (2003) WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Current Opinion in Allergy and Clinical Immunology 3:6, 427-436
CrossRef19
Nuria Andreu, Núria Pujol-Moix, Luis Martinez-Lostao, Marta Oset, Eduardo Muñiz-Diaz, Xavier Estivill, Victor Volpini, Cristina Fillat. (2003) Wiskott–Aldrich syndrome in a female with skewed X-chromosome inactivation. Blood Cells, Molecules, and Diseases 31:3, 332-337
CrossRef20
Luigi D Notarangelo, Hans D Ochs. (2003) Wiskott—Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation. Current Opinion in Immunology 15:5, 585-591
CrossRef21
Jennifer N Luthi, Manish J Gandhi, Jonathan G Drachman. (2003) X-linked thrombocytopenia caused by a mutation in the Wiskott-Aldrich syndrome (WAS) gene that disrupts interaction with the WAS protein (WASP)-interacting protein (WIP). Experimental Hematology 31:2, 150-158
CrossRef22
Hirokazu Inoue, Hidemitsu Kurosawa, Shigeaki Nonoyama, Kohsuke Imai, Hisami Kumazaki, Takayuki Matsunaga, Yuya Sato, Kenichi Sugita, Mitsuoki Eguchi. (2002) X-linked thrombocytopenia in a girl. British Journal of Haematology 118:4, 1163-1165
CrossRef23
Sonja van den Oudenrijn, Marrie Bruin, Claudia C. Folman, James Bussel, Masja de Haas, Albert E. G. KR. von dem Borne. (2002) Three parameters, plasma thrombopoietin levels, plasma glycocalicin levels and megakaryocyte culture, distinguish between different causes of congenital thrombocytopenia. British Journal of Haematology 117:2, 390-398
CrossRef24
Lye Lin Ho, Juliet Ayling, Ian Prosser, Harry Kronenberg, Harry Iland, Douglas Joshua. (2001) Missense C168T in the Wiskott-Aldrich Syndrome protein gene is a common mutation in X-linked thrombocytopenia. British Journal of Haematology 112:1, 76-80
CrossRef25
Mackay, Ian R., Rosen, Fred S., , Buckley, Rebecca H., . (2000) Primary Immunodeficiency Diseases Due to Defects in Lymphocytes. New England Journal of Medicine 343:18, 1313-1324
Full Text26
Brahm H Segal, Thomas L Leto, John I Gallin, Harry L Malech, Steven M Holland. (2000) Genetic, Biochemical, and Clinical Features of Chronic Granulomatous Disease. Medicine 79:3, 170-200
CrossRef27
Takeo Kubota, Satoko Oga, Hirofumi Ohashi, Yasuhiko Iwamoto, Yoshimitsu Fukushima. (1999) B
rjeson-Forssman-Lehmann syndrome in a woman with skewed X-chromosome inactivation. American Journal of Medical Genetics 87:3, 258-261
CrossRef28
D. T. Pilz. (1999) Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. Human Molecular Genetics 8:9, 1757-1760
CrossRef29
Scott B. Snapper, Fred S. Rosen. (1999) THE WISKOTT-ALDRICH SYNDROME PROTEIN (WASP): Roles in Signaling and Cytoskeletal Organization. Annual Review of Immunology 17:1, 905-929
CrossRef30
Mark C. Lanasa, W. Allen Hogge, Eric P. Hoffman. (1999) The X Chromosome and Recurrent Spontaneous Abortion: The Significance of Transmanifesting Carriers. The American Journal of Human Genetics 64:4, 934-938
CrossRef31
Tadashi Ariga, Masafumi Yamada, Takahito Wada, Shinji Saitoh, Yukio Sakiyama. (1999) Detection of lymphocytes and granulocytes expressing the mutant WASP message in carriers of Wiskott-Aldrich syndrome. British Journal of Haematology 104:4, 893-900
CrossRef32
Robert M. Plenge, Lisbeth Tranebjaerg, Peter K.A. Jensen, Charles Schwartz, Huntington F. Willard. (1999) Evidence That Mutations in the X-linked DDP Gene Cause Incompletely Penetrant and Variable Skewed X Inactivation. The American Journal of Human Genetics 64:3, 759-767
CrossRef33
R. E. Buller, A. K. Sood, T. Lallas, T. Buekers, J. S. Skilling. (1999) Association Between Nonrandom X-Chromosome Inactivation and BRCA1 Mutation in Germline DNA of Patients With Ovarian Cancer. JNCI Journal of the National Cancer Institute 91:4, 339-346
CrossRef34
Vanessa Lemahieu, J.M. Gastier, Uta Francke. (1999) Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Human Mutation 14:1, 54-66
CrossRef35
Geneviève de Saint Basile, Marie-Dominique Tabone, Anne Durandy, Florence Phan, Alain Fischer, Françoise Le Deist. (1999) CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization. European Journal of Immunology 29:1, 367-373
CrossRef36
Kathleen E. Sullivan. (1999) Recent advances in our understanding of Wiskott-Aldrich syndrome. Current Opinion in Hematology 6:1, 8
CrossRef37
Omar Racchi, Rosa Mangerini, Davide Rapezzi, Michela Rolfo, Gian Franco Gaetani, Anna Maria Ferraris. (1998) X Chromosome Inactivation Patterns in Normal Females. Blood Cells, Molecules, and Diseases 24:4, 439-447
CrossRef38
Laura Tonon, Gaetano Bergamaschi, Claudia Dellavecchia, Vittorio Rosti, Claudia Lucotti, Lucia Malabarba, Annunziata Novella, Elena Vercesi, Francesco Frassoni, Mario Cazzola. (1998) Unbalanced X-chromosome inactivation in haemopoietic cells from normal women. British Journal of Haematology 102:4, 996-1003
CrossRef39
(1998) X-Linked Wiskott–Aldrich Syndrome in a Girl. New England Journal of Medicine 338:25, 1850-1851
Full Text40
Paul M. Brickell, David R. Katz, Adrian J. Thrasher. (1998) WISKOTT-ALDRICH SYNDROME: CURRENT RESEARCH CONCEPTS. British Journal of Haematology 101:4, 603-608
CrossRef41
Lucio Luzzatto, Anastasios Karadimitris. (1998) Dyskeratosis and ribosomal rebellion. Nature Genetics 19:1, 6-7
CrossRef42
Puck, Jennifer M., , Willard, Huntington F., . (1998) X Inactivation in Females with X-Linked Disease. New England Journal of Medicine 338:5, 325-328
Full Text
- Letters
