Dominantly Transmitted 
-Thalassemia Arising From the Production of
Several Aberrant mRNA Species and One Abnormal Peptide
Paula Faustino,
Leonor Osório-Almeida,
Luísa Romão,
José Barbot,
Berta Fernandes,
Benvindo Justiça, and
João Lavinha
From the Departamento de Genética Humana, Instituto Nacional de
Saúde Dr Ricardo Jorge, Lisboa; the Laboratório de
Genética Molecular, Faculdade de Ciências e Tecnologia,
Universidade Nova de Lisboa, Monte da Caparica; and the Serviço
de Hematologia, Hospital de Santo António, Porto, Portugal.
We describe a dominantly inherited 
-thalassemia intermedia
phenotype observed in a five-generation Portuguese family. Carriers are
characterized by moderate anemia, hypochromia, microcytosis, elevated
hemoglobin (Hb)A2 and HbF levels, splenomegaly,
hepatomegaly, and inclusion bodies in pheripheral red blood cells after
splenectomy. The molecular basis of this condition is a small deletion
within the 5
consensus splicing sequence of the second intron of the -globin gene, IVS-II-4,5 (-AG). Reticulocyte RNA studies performed by reverse transcription-polymerase chain reaction (RT-PCR) and primer
extension analysis showed three abnormally processed transcripts, which, upon sequencing, were shown to correspond to (1) skipping of
exon 2, and (2) activation of two cryptic splice sites (between codons
59/60, and at IVS-II-47). In vitro translation studies of these
patients' reticulocyte RNA have shown that at least one of these
aberrant mRNA species is translated into an abnormally elongated
peptide whose cytotoxic properties could, in part, be causing the
atypical dominant mode of inheritance observed in this family. We
suggest that this elongated chain is unable to combine with an
-globin chain to form a functional Hb molecule. Its degradation
would, then, exhaust the proteolytic defense mechanism of the erythroid
precursors, leading to inefficient proteolysis of the free chains
in excess.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 685-690
© 1998 by The American Society of Hematology.
