Publication Cover
Hemoglobin
international journal for hemoglobin research
Volume 31, 2007 - Issue 2
361
Views
29
CrossRef citations to date
0
Altmetric
Second Titus H.J. Huisman Memorial Symposium: Recent Advances in Hemoglobinopathy, May 8–9, 2006, Adana, Turkey

Dominantly Inherited β-Thalassemia

Pages 193-207 | Published online: 07 Jul 2009
 

Abstract

Dominantly inherited β-thalassemia (thal) or “inclusion body β-thalassemias” are heterogeneous at the molecular level and are due to mutations at or near the β-globin gene locus. Many of these involve mutations of exon 3 of the β-globin gene. They include frameshifts, premature chain termination (nonsense) mutations, and complex rearrangements that lead to the synthesis of truncated or elongated and highly unstable β-globin gene products. The resulting β chain variants are very unstable, and in many cases, the products of the dominantly inherited β-thal are not detectable. Hematological and clinical observations made in several families with comparable forms of β-thal and with certain highly unstable hemoglobin (Hb) variants, have indicated a striking overlap; many subjects with detectable unstable Hb variants and with a dominant type of β-thal without a detectable abnormal Hb, have similar phenotypes. Here, a review of dominantly inherited β-thal is given, and new examples of hyperunstable Hbs (Hb Stara Zagora and Hb Jambol) are presented.

The first example is a hyperunstable variant named Hb Stara Zagora that was found in a 2-year-old Bulgarian boy. The abnormal Hb is associated with severe hemolytic anemia as a consequence of its hyper instability. The anemia was noticed at the age of 2 months and since then he has been on a regular monthly blood transfusion regimen. Hemoglobin analysis revealed no abnormalities, except the presence of inclusion bodies. Sequencing of the β-globin gene revealed a heterozygosity for a 6 bp deletion (−TGGCTA) at codons 137 (the second and third bp), 138 and 139 (the first bp), thus forming a new codon at position 139 (GAT). This event eliminates three amino acids (Val-Ala-Asn) and introduces a new residue (Asp). It creates a new restriction site for HphI. The parents and his twin brother had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.

The second example is a new hyperunstable variant named Hb Jambol, found as a de novo mutation in a 2-year-old Bulgarian girl with severe hemolytic anemia. The mutation was detected through RNA/DNA analysis. It represents a complex genomic rearrangement involving an insertion of 23 nucleotides (nts) after IVS-II-535, a deletion of 310 nts extending from IVS-II-550 to the first nt of codon 108, and an insertion of 28 nts at the deletion junctions (derived from inverted sequence between nts +3707 and +3734 3′ to the β-globin gene termination codon). At the protein level, this mutation leads to a deletion of four amino acid residues (Leu-Leu-Glu-Asn) at positions 105, 106, 107 and 108, and an insertion of nine residues (Val-Pro-Ser-Val-Thr-Leu-Phe-Phe-Asp) at the same location, creating an abnormal elongated β chain of 151 amino acid residues. The parents had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.

Notes

*Presented at the Second Titus H.J. Huisman Memorial Symposium, Adana, Turkey, May 8–9, 2006.

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 65.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 1,628.00 Add to cart

* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.