Equineseverecombinedimmunodeficiency: A defectinV(D)J recombination andDNA-dependent protein kinaseactivity

V(D)Jrearrangement isthemolecular mech- anismbywhichanalmost infinite arrayofspecific immune receptors aregenerated. Defects inthisprocess result in profound immunodeficiency asisthecaseintheC.B-17 SCID mouseorinRAG-1(recombination-activating gene1)or RAG-2deficient mice. Ithasrecently becomeclear thatthe V(D)Jrecombinase mostlikely consists ofbothlymphoid- specific factors andubiquitously expressed components ofthe DNAdouble-strand break repair pathway. Thedeficit inSCID miceisinafactor thatisrequired forbothofthese pathways. Inthisreport, we showthatthefactor defective inthe autosomal recessive severe combined immunodeficiency of Arabian foals isrequired for(i)V(D)Jrecombination, (ii) resistance toionizing radiation, and(iii) DNA-dependent protein kinase activity. During early lymphoid differentiation distinct genesegments called variable (V), diversity (D), andjoining (J) arejoined to formthecoding sequences ofimmunoglobulin andT-cell antigen receptor variable regions. Thisprocess depends upon site-specific somatic recombination andresults intherandom assortment ofvarious combinations ofV,D,andJgene segments (reviewed inrefs. 1-3). Therearrangement process involves twodouble-stranded DNA cutsandsubsequent reli- gations. Thisresults intheformation oftwonewDNA joints-coding joints, whichcontain thecoding information, andsignal joints, whichcontain thetworecombination signal sequences (ref. 3andreferences therein). In1989and1990, twohighly conserved geneswerediscovered, RAG-1and