title: Hypothesis for generation of the unstable Hb Bucuresti (beta 42 Phe-->Leu) mutation.
abstract: BACKGROUND
  Unstable hemoglobin disorders are characterized by a congenital, mostly familial chronic hemolytic anemia with episodes of severe hemolysis during febrile illnesses. Usually, isopropanol and heat stability tests lead to the diagnosis which is confirmed by protein and gene sequencing. Generation of the mutations is still a subject of controversy. PATIENT, MATERIALS AND METHODS: We describe a 6-year-old Swiss child with congenital hemolytic anemia and a negative family history. Hemoglobin was studied by IEF, HPLC reverse phase chromatography, heat stability and isopropranol tests. DNA was sequenced in both coding and non-coding strands.
  
  
  RESULTS
  An unstable Hb was diagnosed on the basis of positive heat stability and isopropranol tests. The TTT-->TTG mutation at codon 42 corresponding to a Phe-->Leu substitution was found on DNA sequencing. Paternity was confirmed indicating that we are dealing with a new mutation.
  
  
  CONCLUSIONS
  So far, three different mutations at codon 42 of the beta-chain, and two at the corresponding position of the alpha-chain have been described, all leading to a hemolytic anemia. These mutations can either represent random phenomena occurring at an important location in the heme pocket, or may be secondary to the two highly homologous zones present in this region. These homologous zones may indicate a hot spot for point mutations created by abnormal crossing over or formation of loops, and an imperfect DNA repair process.
authors.affiliation: Unit of Pediatric Hemato-Oncology, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland. Maya.vonPlanta@hcuge.ch
authors.forename: M
authors.initials: M
authors.lastname: von Planta
authors.forename: J
authors.initials: J
authors.lastname: Humbert
authors.forename: P
authors.initials: P
authors.lastname: Wacker
authors.forename: P C
authors.initials: PC
authors.lastname: Rimensberger
authors.forename: R
authors.initials: R
authors.lastname: Darbellay
authors.forename: E
authors.initials: E
authors.lastname: Roosnek
authors.forename: Y
authors.initials: Y
authors.lastname: Heller
authors.forename: P
authors.initials: P
authors.lastname: Beris
mesh_terms: D019943:Amino Acid Substitution; D000743:Anemia, Hemolytic / Q000209:etiology / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D006455:Hemoglobins, Abnormal / Q000032:analysis / Q000235:genetics*; D006358:Hot Temperature; D006801:Humans; D008297:Male; D017354:Point Mutation; D011489:Protein Denaturation
chemical_list: D006455:Hemoglobins, Abnormal; C059171:hemoglobin Louisville