TYPE HPFH-1; Black (see Fig. 13)
CAUSE An extensive deletion of ~106 kb that includes the delta and beta genes and adjacent DNA. The 5' breakpoint maps at a midpoint of a member of the Alu I family of repetitive sequences located ~4 kb 5' to the delta gene. This deletion is likely caused by these repetitive sequences which may act as 'hot spots' for recombination events and are possibly involved in the regulation of fetal gene expression. The 3' breakpoint is located at ~95 kb from the 3' end of the beta gene. Among the HPFH determinants, the HPFH-1 extends downstream in the 3' region father than any other reported ones.
DETECTION By gene mapping and sequencing. The breakpoints of the deletion have been defined through cloning and sequencing, and through amplification with specific primers,(5-7). Interestingly, an insertion of five nucleotides (AAATA) was observed. The Ggamma chain carries a C->T deletion at position -158 of the promoter sequence (8) resulting in higher than expected Ggamma values in the heterozygote and the homozygote.
PHENOTYPE No hematological abnormalities in the heterozygotes and only a mild erythrocytosis in the homozygote. Only Hb F is present in the homozygote, while compound heterozygotes for HPFH and a beta chain variant (Hbs S, C, or E) or a delta chain variant (Hb B2) do not produce Hb A or Hb A2, because of the absence of beta and delta chain production in cis. The Hb F production in the heterozygotes varies between 20 and 30% (average 24.8± 3.4; n=40), and Hb F contains both the Ggamma and Agamma chains (Ggamma 50.7±4.3; n=40). The level of Hb F is decreased if the heterozygote is (severely) iron deficient (9). HPFH-1 has been observed in combination with beta+-thal resulting in a mild anemia with microcytosis (10).
DISTRIBUTION HPFH-1 is rather common in the Black population, both in Africa and the Americas.
1. Tuan, D., Murnane, M.J., de Riel, J.K., and Forget, B.G.: Nature, 285:335, 1980.
2. Jagadeeswaran, P., Tuan, D., Forget, B.G., and Weissman, S.M.: Nature, 296:469, 1982.
3. Tuan, D., Feingold, E., Newman, M., Weissman, S.M., and Forget, B.G.: Proc. Natl. Acad. Sci. USA, 80:6937, 1983.
4. Kutlar, A., Gardiner, M.B., Headlee, M.G., Reese, A.L., Cleek, M.P., Nagle, S., Sukumaran, P., and Huisman, T.H.J.: Biochem. Genet., 22:21, 1984.
5. Feingold, E.A. and Forget, B.G.: Blood, 74:2178, 1989.
6. Stolle, C.A., Penny, L.A., Ivory, S., Forget, B.G., and Benz, E.J., Jr.: Blood 75:499, 1990.
7. Martinez, G., Hernandez, A., Corral, L., Muniz, A., Alaez, C., Serra, A., Alfarano, A., Saglio, G., and Camaschella, C.: Blood, 76:1262, 1990.
8. Bakioglu, I., Kutlar, A., and Huisman, T.H.J.: Biochem. Genet., 24:149, 1986.
9. Adams, J.G., III, Coleman, M.B., Hayes, J., Morrison, W.T., and Steinberg, M.H.: N. Engl. J. Med., 313: 1402, 1985.
10. Huisman, T.H.J., Schroeder, W.A., Charache, S., Bethlenfalvay, N.C., Bouver, N., Shelton, J.R., Shelton, J.B., and Apell, G.: N. Engl. J. Med., 285:711, 1971.

This material is from the book A Syllabus of Thalassemia Mutations (1997) by Titus H.J. Huisman, Marianne F.H. Carver, and Erol Baysal, published by The Sickle Cell Anemia Foundation in Augusta, GA, USA. Copyright © 1997 by Titus H.J. Huisman. All rights reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, microfilming and recording, or by any information storage and retrieval systems, without permission in writing from the Author.