We have selected Ia variants from the Ia+ (H-2d) M12.4.1 B cell lymphoma that are negative on the cell surface for one or both Ia isotypes. The molecular analysis of two such independently selected cell lines, M12.A2 and M12.C3, is reported here. This analysis revealed that the genes encoding Ad beta (M12.A2) and Ed beta (M12.C3) contained identical single-nucleotide transitions that resulted in the substitution of Ser (mutant) for Asn (wild-type) at residue 82/83 of the extracellular NH2-terminal (membrane distal) beta 1 domain. This conservative substitution caused a cytoplasmic accumulation of I-A or I-E molecules in the respective cell line although predicted secondary-structure analysis suggests a minimal effect on protein conformation. Thus, the mutation appears to have either created a negative signal that stops transport or eliminated a positive signal that is required for transport and targeting to the cell surface.

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