title: Dominantly Inherited beta-Thalassemia.
abstract: Dominantly inherited beta-thalassemia (thal) or "inclusion body beta-thalassemias" are heterogeneous at the molecular level and are due to mutations at or near the beta-globin gene locus. Many of these involve mutations of exon 3 of the beta-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 beta-globin gene products. The resulting beta chain variants are very unstable, and in many cases, the products of the dominantly inherited beta-thal are not detectable. Hematological and clinical observations made in several families with comparable forms of beta-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 beta-thal without a detectable abnormal Hb, have similar phenotypes. Here, a review of dominantly inherited beta-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 beta-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 beta-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 beta chain of 151 amino acid residues. The parents had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.
authors.affiliation: Research Centre for Genetic Engineering and Biotechnology, Macedonian Academy of Sciences and Arts. Skopje, Republic of Macedonia. gde@manu.edu.mk
authors.forename: Georgi D
authors.initials: GD
authors.lastname: Efremov
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D005091:Exons; D005799:Genes, Dominant; D014644:Genetic Variation; D005914:Globins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D003062:Codon; D005914:Globins