Four individuals have been identified, within a single family, who lack phagocyte expression of the high affinity type I IgG receptor (CD64). As a result, their monocytes are unable to support mouse IgG2a anti-CD3-induced T cell mitogenesis (nonresponder individuals). Southern blotting proved all three human Fc gamma receptor I (hFc gamma RI) genes to be present in nonresponders without major structural changes. Nucleotide sequencing showed identical hFc gamma RIA promoter regions in all individuals. At the message level, a distinct difference was noted between monocytes from control (responder) donors and from nonresponders. Both a 1.7- and 1.6-kb message were found in responders, whereas in nonresponders only the 1.6-kb species was detectable. Reverse transcriptase-PCR analyses showed the hFc gamma RIa transcript (encoding a receptor with three extracellular Ig-like domains) to be present at a approximately 15- to 20-fold lower level in nonresponder monocytes. Importantly, we found a single nucleotide difference (C --> T) within the extracellular domain exon 1-encoding region of hFc gamma RIA in nonresponders, resulting in the change of codon 92 (encoding an arginine) into a termination codon. This change likely affects mRNA stability and, thereby, leads to undetectable expression of phagocyte-hFc gamma RIa. Despite this defect, these individuals are apparently healthy, suggesting that hFc gamma RIa is dispensable for phagocyte functioning.