Several congenital immunodeficiency diseases are inherited in an X linked recessive fashion, including the most common forms of severe combined immunodeficiency disease (XSCID) and agammaglobulemia (XLA), as well as Wiskott Aldrich syndrome (WA), X linked lymphoproliferative syndrome (XLP), and hyper- IgM syndrome. Genetic counselling, perinatal management of affected infants and gene mapping would be facilitated if carrier detection tests were available, but female carriers of these diseases are completely normal. Preliminary studies indicate that the normal phenotype of female heterozygotes in XSCID, XLA and WA is due to failure of cells in which the mutant gene is on the active X chromosome to enter the mature cell pool. This finding will form the basis for three approaches to diagnosis of the carrier state. The first requires that the two X chromosomes be separated so that the active and inactive X can be identified by restriction fragment length polymorphisms (RFLPs). This will be achieved with somatic cell hybrids made from HPRT-rodent cells and lymphocytes from carriers and their relatives. Because X chromosome RFLPs are abundant this method of carrier detection will succeed in every women, but less laborious techniques will also be pursued based on DNA methylation patterns and on detection of polymorphisms in RNA. The most efficient technique for assaying X inactivation pattern will be used to determine carrier status of at-risk females. This information will make possible regional localization of XSCID by linkage analysis with RFLPs as well as refinement of the map position of XLA, WA, XLP. Improved carrier ascertainment will also aid genetic studies of heterogeneity, new mutation rates and source of new mutations in X-linked immunodeficiencies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD023679-05
Application #
3323840
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1988-03-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1994-06-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Deschenes, S M; Puck, J M; Dutra, A S et al. (1994) Comparative mapping of canine and human proximal Xq and genetic analysis of canine X-linked severe combined immunodeficiency. Genomics 23:62-8
Puck, J M (1994) Molecular and genetic basis of X-linked immunodeficiency disorders. J Clin Immunol 14:81-9
Puck, J M; Deschenes, S M; Porter, J C et al. (1993) The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet 2:1099-104
Puck, J M; Conley, M E; Bailey, L C (1993) Refinement of linkage of human severe combined immunodeficiency (SCIDX1) to polymorphic markers in Xq13. Am J Hum Genet 53:176-84
Puck, J M; Stewart, C C; Nussbaum, R L (1992) Maximum-likelihood analysis of human T-cell X chromosome inactivation patterns: normal women versus carriers of X-linked severe combined immunodeficiency. Am J Hum Genet 50:742-8
Conley, M E; Burks, A W; Herrod, H G et al. (1991) Molecular analysis of X-linked agammaglobulinemia with growth hormone deficiency. J Pediatr 119:392-7
Henthorn, P S; Stewart, C C; Kadesch, T et al. (1991) The gene encoding human TFE3, a transcription factor that binds the immunoglobulin heavy-chain enhancer, maps to Xp11.22. Genomics 11:374-8
Puck, J M; Stewart, C C; Henthorn, P S (1991) A high-frequency RFLP at the human TFE3 locus on the X chromosome. Nucleic Acids Res 19:684
Puck, J M; Siminovitch, K A; Poncz, M et al. (1990) Atypical presentation of Wiskott-Aldrich syndrome: diagnosis in two unrelated males based on studies of maternal T cell X chromosome inactivation. Blood 75:2369-74

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