Mapping of a gene for X-linked agammaglobulinemia and evidence for genetic heterogeneity

Mensink, E. J. B. M.; Thompson, Allan; Schot, J. D. L.; Greef, W. M. M. van de; Sandkuyl, L. A.; Schuurman, R. K. B.

doi:10.1007/bf00279095

Cited by 55 publications

(22 citation statements)

References 14 publications

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“…and led to investigations of the role of the X chromosome in the genesis of that system. Genes for each of those X-linked immunologic deficiencies were mapped to specific regions of the X chromosome (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Furthermore, in X-linked CGD the resultant protein abnormality, a deficiency in the production of the 90-kD carrier protein for cytochrome b245, was elucidated (29, 30), and a sialic acid rich glycoprotein (GP-1 15) was found to be deficient in certain cases of WAS (31).…”

Section: Introductionmentioning

confidence: 99%

A novel X-linked combined immunodeficiency disease.

Brooks¹,

Schmalstieg²,

Wirt³

et al. 1990

J. Clin. Invest.

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A novel X-linked combined immunodeficiency disease was found in five living males in an extended family in the United States. The age of the affected males ranged from 2.5 to 34 yr. The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections. The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes. Thus, affected males in this family carry an abnormal gene on their X chromosome that results in a combined immunodeficiency that is distinct from previously reported disorders. (J.

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Section: Introductionmentioning

confidence: 99%

A novel X-linked combined immunodeficiency disease.

Brooks¹,

Schmalstieg²,

Wirt³

et al. 1990

J. Clin. Invest.

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“…Our results clearly show that X chromosome-linked SCID, which is thought to involve a defect in T-cell differentiation, is located in a different region than Bruton's agammaglobulinemia (a defect in B-cell maturation) since the latter disease has been mapped very close to markers S21 and pXG12 (20)(21)(22). Analysis of additional families together with a refinement of the genetic map in this area of the human X chromosome should result in a more precise localization of the SCID gene and should thus provide more accurate tools for prenatal and carrier diagnosis and for the ultimate isolation of the SCID gene.…”

Section: Discussionmentioning

confidence: 65%

Close linkage of the locus for X chromosome-linked severe combined immunodeficiency to polymorphic DNA markers in Xq11-q13.

Basile

Arveiler

Oberlé

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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The gene for X chromosome-linked severe combined immunodeficiency (SCID), a disease characterized by a block in early T-cell differentiation, has been mapped to the region Xqll-ql3 by linkage analysis with restriction fragment length polymorphisms. High logarithm of odds (lod) scores were obtained with the marker 19.2 (DXS3) (z = 5.51 at a recombination fraction 0 = 0.11) and with the marker cpX73 (DXS159) that showed complete cosegregation with the disease locus in the informative families analyzed (z = 5.27 at 0 = 0.00). Other significant linkages were obtained with several markers from Xqll to q22. With the help of a recently developed genetic map of the region, it was possible to perform multipoint linkage analysis, and the most likely genetic order is DXS1-(SCID, DXS159)-DXYS1-DXYS12-DXS3, with a maximulm multipoint logarithm of odds score of 11.0. Our results demonstrate that the SCID locus (gene symbol IMD4) is not closely linked to the locus of Bruton's agammaglobulinemia (a defect in B-cell maturation). They also provide a way for a better estimation of risk for carrier and antenatal diagnosis.Severe combined immunodeficiency (SCID) is a syndrome in which affected infants lack both cellular and humoral immunity and die in early life from overwhelming infection if bone marrow transplantation is not performed. X chromosomelinked severe combined immunodeficiency (McKusick no. 30040, also designated IMW4 in the nomenclature of Human Gene Mapping Workshops) is characterized by a complete absence of mature T lymphocytes, suggesting that the disease results from a block in early T-cell differentiation (1). In autosomal recessively transmitted SCID, an absence of both T and B lymphocytes is most often found, although cases of female SCID patients with a complete absence of T cells and normal B-cell numbers have been described (2). Obligatory carrier females of X-linked SCID are immunologically normal, and this impairs genetic counseling. The gene has not previously been localized on the X chromosome. Many restriction fragment length polymorphisms (RFLPs) have been detected on the human X chromosome, and they are increasingly used to establish a genetic map that includes disease genes (3). We have performed a genetic linkage analysis in nine families with clear-cut X-linked SCID by using several RFLP markers, and this has allowed us to map the IMD4 gene to the region Xqll-ql13. This should be an important step toward carrier and prenatal diagnosis and toward isolation of the gene itself.

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“…As these mutations are highly penetrant, traditional genetic linkage studies have been able to isolate the responsible genes and pathways for some of these conditions, many of which have severe or even fatal clinical presentations. Notable examples include the IFN-γ receptor ( IFNGR1 ) in cases of severe mycobacterial infections [7], the lysosomal trafficking regulator ( LYST ) for Chediak-Higashi syndrome [8], and Bruton's tyrosine kinase for X-linked agammaglobulinemia [9,10]. …”

Section: Severe Combined Immune Deficiency and Partial Immune Deficiencymentioning

confidence: 99%

Shared pathways to infectious disease susceptibility?

Khor

Hibberd

2010

Genome Med

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The recent advent of genomic approaches for association testing is starting to enable a more comprehensive understanding of the role of human immune response in determining infectious disease outcomes. Progressing from traditional linkage approaches using microsatellite markers to high-resolution genome-wide association scans, these new approaches are leading to the robust discovery of a large number of disease susceptibility genes and the beginnings of an appreciation of their connections. In this commentary, we discuss how this technology development has led to increasingly complex and common infectious diseases being unraveled, and how this is starting to dissect pathogen-specific human responses. Intriguingly, these still preliminary findings suggest that pathogen innate detection mechanisms may not be as shared among diseases as immune response mechanisms.

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Mapping of a gene for X-linked agammaglobulinemia and evidence for genetic heterogeneity

Cited by 55 publications

References 14 publications

A novel X-linked combined immunodeficiency disease.

A novel X-linked combined immunodeficiency disease.

Close linkage of the locus for X chromosome-linked severe combined immunodeficiency to polymorphic DNA markers in Xq11-q13.

Shared pathways to infectious disease susceptibility?

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