Novel compound heterozygote mutation in two siblings with scid jak3 mutations

Poster Presentations
Novel compound heterozygote mutation in two siblings with SCID JAK3 mutations
Hans H. Shuhaiber, M.D. 1, Edwin Guzman, M.S. 1, Kwame Anyane-Yeboa, M.D. 1, Jennifer M. Puck, M.D. 2
1Pediatrics, Columbia University Medical Centre, New York, N.Y., United States, 2Pediatrics, UCSF School of Medicine, San Francisco, C.A., United States During the last 15 years, an increasing number of genes has been identified whose abnormalities account for primary immunodeficiencies, defects in development and/or function of the immune system. Severe combined immunodeficiency (SCID), estimated to occur in 1/50,000 to 1/100,000 births, is most often caused by defects of the X-linked common γ chain (γc) of cytokine receptors, part of the receptor complexes for interleukin (IL-) 2, IL-4, IL-7, IL-9, and IL-15. Males with X-SCID usually have very few T and NK cells and functionally defective B-cells (T-B+NK- SCID). An identical immunologic phenotype is seen in autosomal recessive SCID due to mutations in the JAK3 gene, encoding a tyrosine kinase that is functionally coupled to γc (MIM# 600173). We describe two brothers, who were healthy at birth, but then suffered from persistent and recurrent infections. The older male was hospitalized at 8 months of age with recurrent bronchiolitis, thrush, and severe rotavirus enteritis. His immune workup showed absent T cells, 13 NK cells/ul (normal range 170-830) and 414 B cells (nl 430-3000) with low to absent immunoglobuins. His younger brother was diagnosed at 3 months, after developing fever, mucositis and recurrent infections; his lymphocyte profile, obtained once his brother’s history was appreciated, showed undetectable T cells, 29 NK cells, and 612 B cells. Both boys had normal γc gene sequence. They were compound heterozygotes for two previously unreported JAK3 mutations, a paternally inherited single codon deletion (c.2000delTCA; p.Ile667del) and a maternally inherited missense mutation (c.1851T>C; p.Leu584Pro). Both mutations are in regions that are highly conserved between species and are predicted to be probably damaging to protein function. The older brother received an unrelated cord blood transplant after Fludarabine, ATG, and Cytoxan conditioning and is growing, healthy, and off all medications three years later. The younger brother is currently undergoing allogenic unmatched cord blood transplantation. Our cases identify two new disease-associated mutations in the cell signaling protein JAK3. Relatively few JAK3 mutations have been published, and the true incidence is unknown. However, JAK3 defects are caused 15% of all SCID in published series. Availability of a molecular diagnostic test, based on amplification and sequencing of genomic DNA, makes gene diagnosis for SCID possible, and has permitted recognition that JAK3 deficiency is not always associated with a T-B+NK- phenotype. The approach of Puck et al. to quantitate T cell receptor excision circles (TRECs) by PCR on DNA extracted from dried blood spots obtained for newborn screening can detect infants with T cell lymphopenia (Routes et al., JAMA 2009); thus newborn screening for SCID and other T cell defects can identify infants before infectious complications occur. If testing for TRECs were incorporated into state newborn screening programs infants such as the ones reported here could avoid serious infections and receive early diagnosis and therapy.


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