title: Hb St. Jozef, A Val-->Leu N-terminal mutation leading to retention of the methionine, and partial acetylation found in the globin gene in Cis with a -alpha3.7 thalassemia deletion.
abstract: We report a new hemoglobin (Hb) variant found in a 6-year-old girl of Moroccan origin, living in the Dutch city of Gouda. The child was referred because of microcytic and hypochromic parameters. A normal zinc protoporphyirin (ZPP) value excluded iron deficiency and gap-polymerase chain reaction (gap-PCR) revealed a heterozygosity for the common -alpha(3.7) thalassemia deletion, partially justifying the hematological picture. The Hb pattern on alkaline electrophoresis and capillary electrophoresis was normal, while a fraction of 9% preceding the Hb A peak, remained visible on different high performance liquid chromatography (HPLC) devices. This fraction, located in front of the Hb A peak, is usually considered as a Hb A derivate that becomes more expressed in older samples. However, the sample was freshly collected and the peak unusually evident. Therefore, direct sequencing of the alpha-globin genes was performed revealing a GTG-->CTG transversion at codon 1 of the alpha1-globin gene or of the hybrid gene. This point mutation induces a single amino acid substitution from valine to leucine. Electrospray-mass spectrometry (ES-MS) analysis revealed, in addition to this substitution, that the N-terminal methionine was retained and that about 20% of the variant was acetylated. As expected for an association with a -alpha(3.7)-thalassemia (thal) deletion, the non acetylated and acetylated abnormal alpha chain amounted to 32% of the total alpha chains. Family studies revealed that the mutated codon was located in cis of the deletion.
authors.affiliation: The Hemoglobinopathies Laboratory, Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cornelis L
authors.initials: CL
authors.lastname: Harteveld
authors.forename: Florens G A
authors.initials: FG
authors.lastname: Versteegh
authors.forename: Eduard H G
authors.initials: EH
authors.lastname: van Leer
authors.forename: Jaap S
authors.initials: JS
authors.lastname: Starreveld
authors.forename: Peter J M J
authors.initials: PJ
authors.lastname: Kok
authors.forename: Irene
authors.initials: I
authors.lastname: van Rooijen-Nijdam
authors.forename: Peter
authors.initials: P
authors.lastname: van Delft
authors.forename: Isabelle
authors.initials: I
authors.lastname: Zanella-Cleon
authors.forename: Michel
authors.initials: M
authors.lastname: Becchi
authors.forename: Henri
authors.initials: H
authors.lastname: Wajcman
authors.forename: Piero C
authors.initials: PC
authors.lastname: Giordano
mesh_terms: D000107:Acetylation; D019943:Amino Acid Substitution; D002648:Child; D005192:Family Health; D005260:Female; D005914:Globins / Q000235:genetics*; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D008715:Methionine; D009154:Mutation; D017384:Sequence Deletion; D013789:Thalassemia / Q000235:genetics*
chemical_list: D006455:Hemoglobins, Abnormal; C523159:hemoglobin St. Jozef; D005914:Globins; D008715:Methionine