Patients with leukocyte adhesion molecule (CD11/CD18, beta 2 integrins) deficiency have structural defects in the common beta subunit (CD18), which prevent heterodimer formation and normal cell surface expression of these receptors, leading to life-threatening bacterial infections. To elucidate the nature of these defects in a patient with partial (type II) deficiency, abnormal CD18 cDNA clones were isolated, using the polymerase chain reaction to amplify the patient's B cell-derived cDNAs. Sequence analysis revealed two mutant alleles. cDNA clones, representing a maternal allele, contained both a 12-base pair insertion resulting in an in-frame addition of four amino acids between P247 and E248 and a C1756----T nucleotide transition, resulting in an R586----W substitution in the normal CD18 protein. The inframe insertion arose by a single nucleotide C----A transversion in the 3' terminus of an intron, generating aberrant splice acceptor site. Other cDNA clones contained an A1052----G nucleotide transition not present in either parent which resulted in an N351----S substitution. To determine the functional importance of these changes, cDNA encoding a normal alpha chain (CD11b) was cotransfected into COS with CD18 cDNAs encoding for wild-type, maternal mutant allele, or CD18 containing N351----S substitution. Immunostaining of transfectants with anti-CD18 monoclonal antibodies revealed no cell surface expression of the maternal mutant CD18, and 22% surface expression of N351----S CD18. Both the insertion and the N351----S mutations occurred in a 250 amino acid extracellular region of CD18 that is highly conserved among beta integrins supporting a role for this region in heterodimer formation.