Carrier detection in the Wiskott Aldrich syndrome

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by immunodeficiency and severe thrombocytopenia in affected males, but no demonstrable clinical abnormalities in carrier females. Through analysis of the methylation patterns of X-linked genes that display restriction fragment length polymorphisms (RFLPs), we studied the pattern of X-chromosome inactivation in various cell populations from female relatives of patients with WAS. The peripheral blood T cells, granulocytes, and B cells of eight obligate WAS carriers were found to display specific patterns of X-chromosome inactivation clearly different from these of normal controls. Thus, carriers of WAS could be accurately identified using this analysis.

Download Full-text

Carrier detection in the Wiskott Aldrich syndrome

Blood ◽

10.1182/blood.v72.5.1735.1735 ◽

1988 ◽

Vol 72 (5) ◽

pp. 1735-1739 ◽

Cited By ~ 63

Author(s):

ER Fearon ◽

DB Kohn ◽

JA Winkelstein ◽

B Vogelstein ◽

RM Blaese

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Cell Populations ◽

Severe Thrombocytopenia ◽

Wiskott Aldrich Syndrome ◽

Length Polymorphisms ◽

Methylation Patterns ◽

Normal Controls ◽

Restriction Fragment Length

Abstract The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by immunodeficiency and severe thrombocytopenia in affected males, but no demonstrable clinical abnormalities in carrier females. Through analysis of the methylation patterns of X-linked genes that display restriction fragment length polymorphisms (RFLPs), we studied the pattern of X-chromosome inactivation in various cell populations from female relatives of patients with WAS. The peripheral blood T cells, granulocytes, and B cells of eight obligate WAS carriers were found to display specific patterns of X-chromosome inactivation clearly different from these of normal controls. Thus, carriers of WAS could be accurately identified using this analysis.

Download Full-text

Investigation of variability among mouse aggregation chimaeras and X-chromosome inactivation mosaics

Development ◽

10.1242/dev.84.1.309 ◽

1984 ◽

Vol 84 (1) ◽

pp. 309-329

Author(s):

John D. West ◽

Theodor Bücher ◽

Ingrid M. Linke ◽

Manfred Dünnwald

Keyword(s):

X Chromosome ◽

Phosphoglycerate Kinase ◽

X Chromosome Inactivation ◽

Yolk Sac ◽

X Inactivation ◽

Chromosome Inactivation ◽

Cell Populations ◽

Primitive Endoderm ◽

Female Progeny ◽

Positive Correlations

Mouse aggregation chimaeras were produced by aggregating C3H/HeH and C3H/HeHa—Pgk-1a/Ws embryos. At mid-term the proportions of the two cell populations in these conceptuses and the X-inactivation mosaic female progeny of C3H/HeH ♀ × C3H/HeHa—Pgk-1a/Ws ♂ matings were estimated using quantitative electrophoresis of phosphoglycerate kinase (PGK-1) allozymes. The percentage of PGK-1B was more variable in the foetus, amnion and yolk sac mesoderm of the chimaeras than in the corresponding tissues of the mosaic conceptuses. Positive correlations were found for the percentage of PGK-1B between these three primitive ectoderm tissues in both chimaeras and mosaics and between the two primitive endoderm tissues (yolk sac endoderm and parietal endoderm) of the chimaeras. There was no significant correlation between the primitive ectoderm and primitive endoderm tissues of the chimaeras. The results suggest that unequal allocation of cell populations to the primitive ectoderm and primitive endoderm considerably increases the variability among chimaeras but variation probably exists before this segregation occurs. The variation that arises before and at this allocation event is present before X-chromosome inactivation occurs in the primitive ectoderm lineage and explains why the proportions of the two cell populations are more variable among chimaeras than mosaics. Additional variation arises within the primitive ectoderm lineage, after X-inactivation. This variation may be greater in chimaeras than mosaics but the evidence is inconclusive. The results also have some bearing on the nature of the allocation of cells to the primitive ectoderm and primitive endoderm lineages and the timing of X-chromosome inactivation in the primitive ectoderm lineage.

Download Full-text

Changes in DNA methylation during mouse embryonic development in relation to X-chromosome activity and imprinting

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1990.0013 ◽

1990 ◽

Vol 326 (1235) ◽

pp. 299-312 ◽

Cited By ~ 68

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Embryonic Development ◽

X Chromosome ◽

De Novo ◽

Germ Line ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Chromatin Configuration ◽

Methylation Patterns

Changing DNA methylation patterns during embryonic development are discussed in relation to differential gene expression, changes in X-chromosome activity and genomic imprinting. Sperm DNA is more methylated than oocyte DNA, both overall and for specific sequences. The methylation difference between the gametes could be one of the mechanisms (along with chromatin structure) regulating initial differences in expression of parental alleles in early development. There is a loss of methylation during development from the morula to the blastocyst and a marked decrease in methylase activity. De novo methylation becomes apparent around the time of implantation and occurs to a lesser extent in extra-embryonic tissue DNA. In embryonic DNA, de novo methylation begins at the time of random X-chromosome inactivation but it continues to occur after X-chromosome inactivation and may be a mechanism that irreversibly fixes specific patterns of gene expression and X-chromosome inactivity in the female. The germ line is probably delineated before extensive de novo methylation and hence escapes this process. The marked undermethylation of the germ line DNA may be a prerequisite for X-chromosome reactivation. The process underlying reactivation and removal of parent-specific patterns of gene expression may be changes in chromatin configuration associated with meiosis and a general reprogramming of the germ line to developmental totipotency.

Download Full-text

Case Report: Wiskott-Aldrich Syndrome Caused by Extremely Skewed X-Chromosome Inactivation in a Chinese Girl

Frontiers in Pediatrics ◽

10.3389/fped.2021.691524 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xuening Hou ◽

Jie Sun ◽

Chen Liu ◽

Jihong Hao

Keyword(s):

X Chromosome ◽

Clinical Manifestations ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Exon 2 ◽

Wiskott Aldrich Syndrome ◽

Chinese Girl ◽

Skewed X Chromosome Inactivation ◽

Female Carriers

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of Wiskott-Aldrich syndrome protein due to WAS gene mutation, which is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high risk of autoimmune complications and hematological malignancies. Although affected males with WAS usually manifest severe symptoms, female carriers have no significant clinical manifestations. Here, we describe a Chinese girl diagnosed with WAS carrying a heterozygous missense mutation in exon 2 of the WAS gene. The patient presented with persistent thrombocytopenia with small platelets and decreased WAS protein detected by flow cytometry and western blot analysis. The methylation analysis of the HUMARA gene displayed an extremely skewed X-chromosome inactivation (SXCI) pattern, where the X-chromosomes bearing normal WAS gene were predominantly inactivated, leaving the mutant gene active. Hence, our results suggest that completely inactivating the unaffected paternal X-chromosomes may be the reason for such phenotype in this female patient. SXCI has important implications for genetic counseling of female carriers with a family history of WAS.

Download Full-text

Atypical presentation of Wiskott-Aldrich syndrome: diagnosis in two unrelated males based on studies of maternal T cell X chromosome inactivation [see comments]

Blood ◽

10.1182/blood.v75.12.2369.bloodjournal75122369 ◽

1990 ◽

Vol 75 (12) ◽

pp. 2369-2374 ◽

Cited By ~ 1

Author(s):

JM Puck ◽

KA Siminovitch ◽

M Poncz ◽

CR Greenberg ◽

M Rottem ◽

...

Keyword(s):

T Cell ◽

X Chromosome ◽

Hereditary Disease ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Negative Family History ◽

Wiskott Aldrich Syndrome ◽

Inactivation Pattern ◽

Skewed X Chromosome Inactivation ◽

Cell Defect

Congenital thrombocytopenia may occur in isolation or accompanied by eczema and immunodeficiency, as part of the X-linked hereditary Wiskott- Aldrich syndrome (WAS). Because the clinical and immunologic picture of WAS is variable, particularly early in life, definite diagnosis cannot always be made in cases with a negative family history. Two unrelated males with sporadic congenital thrombocytopenia had only questionable immunologic abnormalities as infants, making them clinically indistinguishable from cases of isolated thrombocytopenia, although one developed episodic neutropenia and the other began to manifest a multisystem autoimmune disease at 2 years of age. Evaluation of X chromosome inactivation in the T cells of both patients' mothers showed each of these women to have the same highly skewed X chromosome inactivation pattern seen in carriers of typical familial WAS. A T-cell defect was subsequently directly demonstrated in the second patient, whose lymphocytes failed to proliferate to periodate and anti-CD43. Taken together, these data suggest the presence of T cell immunodeficiency consistent with WAS in these patients. Furthermore, their mothers were found to have a very high likelihood of being carriers, lending support to the diagnosis of a hereditary disease in these boys and making possible genetic prediction in other family members and subsequent pregnancies.

Download Full-text

WISKOTT-ALDRICH SYNDROME (WAS) CARRIER DETECTION BY X-CHROMOSOME INACTIVATION ANALYSIS

Pediatric Research ◽

10.1203/00006450-198704010-00875 ◽

1987 ◽

Vol 21 (4) ◽

pp. 313A-313A ◽

Cited By ~ 2

Author(s):

Donald B Kohn ◽

Eric R Fearon ◽

Jerry A Winklestein ◽

Bert Vogelstein ◽

R Michael Blaese

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Carrier Detection ◽

Chromosome Inactivation ◽

Wiskott Aldrich Syndrome

Download Full-text

Wiskott–Aldrich syndrome in a female with skewed X-chromosome inactivation

Blood Cells Molecules and Diseases ◽

10.1016/s1079-9796(03)00168-2 ◽

2003 ◽

Vol 31 (3) ◽

pp. 332-337 ◽

Cited By ~ 23

Author(s):

Nuria Andreu ◽

Núria Pujol-Moix ◽

Luis Martinez-Lostao ◽

Marta Oset ◽

Eduardo Muñiz-Diaz ◽

...

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Wiskott Aldrich Syndrome ◽

Skewed X Chromosome Inactivation

Download Full-text

Wiskott-Aldrich syndrome in a female

Blood ◽

10.1182/blood-2002-02-0388 ◽

2002 ◽

Vol 100 (8) ◽

pp. 2763-2768 ◽

Cited By ~ 35

Author(s):

Maxim I. Lutskiy ◽

Yoji Sasahara ◽

Dianne M. Kenney ◽

Fred S. Rosen ◽

Eileen Remold-O'Donnell

Keyword(s):

T Cells ◽

X Chromosome ◽

Blood Cells ◽

Mononuclear Cells ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Wild Type ◽

Wiskott Aldrich Syndrome ◽

Blood Mononuclear Cells ◽

Disease Free

Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by thrombocytopenia, eczema, and various degrees of immune deficiency. Carriers of mutated WASP have nonrandom X chromosome inactivation in their blood cells and are disease-free. We report data on a 14-month-old girl with a history of WAS in her family who presented with thrombocytopenia, small platelets, and immunologic dysfunction. Sequencing of the WASP gene showed that the patient was heterozygous for the splice site mutation previously found in one of her relatives with WAS. Sequencing of all WASP exons revealed no other mutation. Levels of WASP in blood mononuclear cells were 60% of normal. Flow cytometry after intracellular staining of peripheral blood mononuclear cells with WASP monoclonal antibody revealed both WASPbright and WASPdimpopulations. X chromosome inactivation in the patient's blood cells was found to be random, demonstrating that both maternal and paternal active X chromosomes are present. These findings indicate that the female patient has a defect in the mechanisms that lead in disease-free WAS carriers to preferential survival/proliferation of cells bearing the active wild-type X chromosome. Whereas the patient's lymphocytes are skewed toward WASPbright cells, about 65% of her monocytes and the majority of her B cells (CD19+) are WASPdim. Her naive T cells (CD3+CD45RA+) include WASPbrightand WASPdim populations, but her memory T cells (CD3+CD45RA−) are all WASPbright. After activation in vitro of T cells, all cells exhibited CD3+CD45RA− phenotype and most were WASPbright with active paternal (wild-type) X chromosome, suggesting selection against the mutated WASP allele during terminal T-cell maturation/differentiation.

Download Full-text