A novel beta-globin structural mutant, Hb Brescia (beta 114 Leu-Pro), causing a severe beta-thalassemia intermedia phenotype.
This study describes a patient with a thalassemia intermedia-like phenotype in whom beta-globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T-C substitution at codon 114 of the beta-globin gene arising as a de novo mutation. The abnormal variant was designated Hb Brescia after the place of birth of the propositus. Normal sequences were detected at the in trans beta-globin locus. In addition, alpha-globin gene analysis detected a triple alpha-globin locus which was inherited from the father. The T-C change at position 114 of the beta-globin gene results in a leucine to proline substitution (Leu-Pro) in the G-helix. The resulting Hb tetramer is highly unstable and precipitates forming inclusion bodies in the peripheral red blood cells. Moreover, the Leu-Pro substitution interferes negatively with the four alpha 1 beta 1 contact points of the G-helix most likely adversely affecting the alpha beta dimer formation. The very severe phenotype presented by our patient is unusual in a heterozygote for an unstable Hb variant and may be explained by the coinheritance of the triple alpha-globin locus.
Murru
S
S
Istituto di Clinica e Biologia dell'Età Evolutiva, Università degli Studi di Cagliari, Italy.
Poddie
D
D
Sciarratta
G V
GV
Agosti
S
S
Baffico
M
M
Melevendi
C
C
Pirastu
M
M
Cao
A
A
D000293:Adolescent; D001483:Base Sequence; D004912:Erythrocytes / Q000502:physiology; D005260:Female; D005914:Globins / Q000235:genetics*; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D007558:Italy; D007930:Leucine; D046911:Macromolecular Substances; D008297:Male; D008969:Molecular Sequence Data; D011392:Proline; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics*
D006455:Hemoglobins, Abnormal; D046911:Macromolecular Substances; C080993:hemoglobin Brescia; D005914:Globins; D011392:Proline; D007930:Leucine