The Clinical And Molecular Diagnosis Of JAK3Deficiency And Reticular Dysgenesis (RD)

Object To establish the gene diagnosis of JAK3deficiency, report the firstJAK3deficiency patient in China and to have literature review. Furthermore,discuss the clinical, immunological and molecular characteristics of JAK3deficiency.Methods Four patients’(P1-4) blood samples were collected who weresuspected of JAK3deficiency, fromApril to October,2011in Children’sHospital of Chongqing Medical University. All of them were detected withPCR amplification and sequencing of JAK3gene. Patient who had JAK3mutation would have family analysis, single nucleotide polymorphism（SNPs）and TCRVβ analysis.Result Four patients almost have the same immunophenotype and clinicalsymptoms. However, only P1was confirmed as a compound heterozygousmutation，both alleles were missense mutations. One allele (1308G＞A;R403H） located in the ninth exon of JAK3， which came from her father， the other allele (3354G＞A; R1085Q）located in the twenty-fourth exon ofJAK3， which came from her mother. Her parents and grandmother werecarries. We confirmed these mutations were disease-caused mutations notSNPs by sequencing the9thand24thexon of JAK3gene of twenty commonpeople. Unfortunately，we failed to detect The TCRVβ of this patient becauseof the limited number of circulating T cells. Up to2007, thirty mutations andthirty five patients had been registered for JAK3deficiency in JAK3base.Their immunophenotype is uniformly T-B+NK-SCID, but the clinicalphenotype of them varied from classical severe combined immunodeficiencydisease (SCID) to almost normal.Conclusion JAK3deficiency is a rare autosomal recessive SCID,characterized by recurrent bacteria and virus infection, absence of T and NKcells but normal number of poorly functioning B cells in the peripheral blood.The diagnosis depends on stat5phosphorylation, sequencing of JAK3geneand detect the JAK3protein by western blot or flow cytometry, when JAK3deficiency is suspected. The most effective treatment of JAK3deficiency ishematopoietic stem cell transplantation (HSCT) and patients who don’treceive HSCT will usually die in infancy. Object To establish the gene diagnosis of RD, report the first RD patient inChina and to have literature review. Furthermore, discuss the clinical,immunological and molecular characteristics of RD.Methods One suspected patient and her parents’ blood samples werecollected during October,2011in Children’s Hospital of Chongqing MedicalUniversity. All of them were detected with PCR amplification and AK2genesequencing.Result The patient’s adenylate kinase2（AK2） gene was confirmed ashomozygous mutantation, which consisted of a missense mutation(c.118A＞G;p.Y12G) and a frame shift mutation(c.129delA，c.131—137delCCGGGCC; p.I16profsX10). Her parents were carries. RD was first found to be caused byAK2mutation in2009, and up to now, thirteen patients and twelve mutationshad been reported. The mutations include frame shift mutation, missensemutation and splicing site mutation.Conclusion RD is an extremely rare autosomal recessive SCID caused byAK2mutation. It’s the most severe form of SCID characterized by recurrentbacteria and virus infection, absence of granulocytes and lymphocytes,whereas platelets and red blood cells count are generally normal in peripheral blood. In bone marrow of individuals with RD would find an earlydifferentiation arrest in myeloid, whereas erythrocytic and megakaryocyticmaturation is almost normal. Thymus dysgenesis is common in X-ray of RDpatient. In addition, affected newborns have bilateral sensorineural deafness.The diagnosis depends on sequencing AK2gene and detecting the AK2protein by western blot or flow cytometry, when RD is suspected. The mosteffective treatment of RD is hematopoietic stem cell transplantation (HSCT)and patients who don’t receive HSCT will usually die in several days ormonths after birth.