Molecular basis for Rh-null syndrome: Identification of three new missensemutations in the Rh50 glycoprotein gene

Rh-null is a rare autosomal recessive disorder characterized by an absence of Rh antigens and a varying degree of hemolytic anemia and spherostomatocy tosis. We report studies of two Japanese Rh-null cases and describe three n ew missense mutations of RHAG, the locus that encodes Rh50 glycoprotein and modulates Rh antigen expression, In Rh-null(HT), RHAG harbored in exon 6 t wo G-->A transitions, (G) under bar TT-->(A) under bar TT and (G) under bar GA-->(A) under bar GA, which cause Val(270)-->Ile and Gly(280)-->Arg subst itutions, respectively. These missense mutations were cotransmitted from th e propositus to the children and were predicted to reside in endoloop 5 and transmembrane (TM) segment 9, respectively, In Rh-null(WO), RHAG contained in exon 9 a single G-->T transversion, G (G) under bar T-->G (T) under bar T, which caused a Gly(380)-->Val missense change in TM12 segment, The G--> T transversion, which is located at the +1 position of exon 9, had also aff ected pre-mRNA splicing and caused partial exon skipping, Although both Rh- null cases had a structurally normal RH antigen locus, hemagglutination and immunoblotting showed no expression of Rh antigens or proteins. These resu lts correlate each mutation with a structural defect in the respective TM d omain of Rh50 glycoprotein. Am, J. Hematol, 62:25-32, 1999, (C) 1999 Wiley- Liss, Inc.