A novel large deletion and single nucleotide insertion in the Wiskott-Aldrich syndrome protein gene.

Deletion mutations of WAS are relatively rare and the precise localization of large deletions in the genome has rarely been described in previous studies. We report here a 5-month-old boy with a large deletion mutation in WAS that completely abolished protein expression. To localize the deletion, a 2816-bp-length sequence that spans between exons 9 and 12 was amplified. PCR amplification of the patient's sample revealed a single band of about 1 kb in contrast to the 2816-bp-amplicon in the control. Genomic DNA sequencing of the patient revealed a 1595-bp-deletion and an adenine insertion (g.5247_6841del1595insA). This large deletion of WAS resulted in partial loss of exon 10 and intron 11, and a complete loss of intron 10 and exon 11.

[Subcutaneous immunoglobulin substitution and therapy]. / Szubkután immunglobulin-pótlás és -terápia.

Patients with combined primary immunodeficiency or B-cell deficiency with low serum concentration of immunoglobulin G can be efficiently treated with immunoglobulin G concentrates. From the 1950s IgG was used intramuscularly, and from the 1980s intravenous immunoglobulin (IVIG) replacement has become widely available for replacement therapy. Among the potential side effects of IVIG (including anaphylaxis), further disadvantages of IVIG are hospitalization during treatment and varying concentrations of IgG. Over the past ten years, subcutaneous IgG (SCIG) preparations have become reasonable alternatives to IVIG. SCIG given weekly assures a more balanced serum IgG level, side affects are mostly local and temporary; systemic, severe adverse events have not been observed. In addition, SCIG can be used for home treatment of patients which improves their quality of life remarkably.

[Management of Fabry disease]. / Fabry-betegség - terápiás útmutató

Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive and the first symptoms usually present in childhood. Consequences of the disease are disability and premature death. The disease in females could be as severe as in males although women may be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline has been summarized by a Hungarian multi-disciplinary working group consisting of physicians who are involved in diagnosis and care of Fabry patients. Previous clinical studies, published articles, and recently established international treatment guidelines were reviewed by the group.

[Wiskott-Aldrich syndrome]. / Wiskott-Aldrich-szindróma.

The Wiskott-Aldrich syndrome is a rare X-linked recessive immunodeficiency disorder characterized by thrombocytopenia and small-sized platelets, eczema and recurrent infections. This paper describes molecular pathology, diagnostics and therapy of the syndrome.

Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome.

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. WAS is caused by mutations in the WASP gene which encodes WASP, a 502-amino acid protein. WASP plays a critical role in actin cytoskeleton organization and signalling, and functions of immune cells. We present here the results of genetic analysis of patients with WAS from eleven Eastern and Central European (ECE) countries and Turkey. Clinical and haematological information of 87 affected males and 48 carrier females from 77 WAS families were collected. The WASP gene was sequenced from genomic DNA of patients with WAS, as well as their family members to identify carriers. In this large cohort, we identified 62 unique mutations including 17 novel sequence variants. The mutations were scattered throughout the WASP gene and included single base pair changes (17 missense and 11 nonsense mutations), 7 small insertions, 18 deletions, and 9 splice site defects. Genetic counselling and prenatal diagnosis were applied in four affected families. This study was part of the J Project aimed at identifying genetic basis of primary immunodeficiency disease in ECE countries. This report provides the first comprehensive overview of the molecular genetic and demographic features of WAS in ECE.

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/ß, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/ß, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.