Rhnull Disease: The Amorph Type Results From a Novel
Double Mutation in RhCe Gene on D-Negative Background
Cheng-Han Huang,
Ying Chen,
Marion E. Reid, and
Christine Seidl
From the Laboratories of Biochemistry and Molecular Genetics and
Immunochemistry, Lindsley F. Kimball Research Institute, New York Blood
Center, New York, NY; and the Laboratory of Immunogenetics and Tissue
Typing, Frankfurt, Germany.
Rhnull disease, which includes the amorph and regulator
types, is a rare genetic disorder characterized by stomatocytosis and
chronic hemolytic anemia. We studied here a German family transmitting
a putative amorph Rhnull disease gene and identified a rare
mutation causing the loss-of-function phenotype. We analyzed the
genomic and transcript structure of RH30, RH50, and
CD47, the three loci thought to be most critical for expression
of the Rh complex in the red blood cell membrane. We showed that in
this family the Rh50 and CD47 transcripts were normal in primary
sequence. However, the RH30 locus contained an unusual double
mutation in exon 7 of the RhCe gene, in addition to a deletion of the
RhD gene. The mutation targeted two adjacent codons in multiple
arrangements probably via the mechanism of microgene conversion. One
scheme entails a noncontiguous deletion of two nucleotides,
[ATT(Ile322)
AT] and [CAC(His323)CC],
whereas the other involves a TC transition [ATT(Ile322)ATC] and a dinucleotide deletion
[CAC(His323)C]. They caused the same shift in open
reading frame predicted to encode a shortened protein with 398 amino
acids. The loss of two transmembrane domains and gain of a new
C-terminal sequence are likely to alter the protein conformation and
impair the Rh complex assembly. Our findings establish the molecular
identity of an amorph Rhnull disease gene, showing that
Rh30 and Rh50 are both essential for the functioning of the Rh
structures as a multisubunit complex in the plasma membrane.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 664-671
© 1998 by the American Society of Hematology.
