Point mutations impairing cell surface expression of the common beta subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM) deficiency.

Abstract

The leukocyte adhesion molecules CD11a/CD18, CD11b/ CD18, and CD11c/CD18 (Leu-CAM) are members of the integrin receptor family and mediate crucial adhesion-dependent functions in leukocytes. The molecular basis for their deficient cell surface expression was sought in a patient suffering from severe and recurrent bacterial infections. Previous studies revealed that impaired cell surface expression of Leu-CAM is secondary to heterogeneous structural defects in the common ft subunit (CD18). Cloning and sequencing of complementary DNA encoding for CD18 in this patient revealed two mutant alleles, each representing a point mutation in the coding region of CD18 and resulting in an amino acid substitution. Each mutant allele results in impaired CD18 expression on the cell surface membrane of transfected COS M6 cells. One substitution involves an arginine residue (Arg5" -cysteine) that is conserved in the highly homologous fourth cysteine-rich repeats of other mammalian integrin subfamilies. The other substitution involves a lysine residue (Lys"' --threonine) located within another highly conserved region in integrins. These data identify crucial residues and regions necessary for normal cell surface expression of CD18 and possibly other integrin ft subunits and define a molecular basis for impaired cell surface expression of CD18 in this patient. (J. Clin. Invest. 1990. 85:977-981.) leukocyte adhesion molecules * integrins -inflammatory response * molecular cloning -genetics

Structure-Function of the Putative I-domain within the Integrin β2 Subunit

“…Surface Expression and Heterodimer Formation-A large number of natural mutations occur within the ␤ 2 I-domain, which abolish surface expression and/or heterodimer formation (31)(32)(33)(34)(35)(36)(37). Nevertheless, when the ␤ 2 mutants were co-transfected with wild-type ␣ M in human kidney 293 cells, all 16 mutants were expressed on the cell surface as heterodimers and the subunits had appropriate molecular weights.…”

The Role of the CPNKEKEC Sequence in the β2 Subunit I Domain in Regulation of Integrin αLβ2 (LFA-1)

“…As the K174T mutation also causes constitutive activation of LFA-1, as described in this study, it may be particularly important in maintaining the "off" contact of the CPNKEKEC loop. This mutation has been found as a missense mutation in a leukocyte adhesion deficiency-1 patient (36).…”

Infectious diseases associated with complement deficiencies

“…These range from the failure to produce mRNA in some individuals with severe disease to the production of specific mRNA that is reduced in quantity, altered in size, or apparently normal. Aberrant splicing has been described in individuals with abnormally sized 13-chain mRNA (198), whereas point mutations have been defined in affected individuals with mRNA of an appropriate size (13). These defects affect widely separated but highly conserved portions of the primary structure of the mature 13 chain.…”