Abstract
Hb Puttelange [β140(H18)Ala→Val] was found as a de novo mutation in two siblings of a French family suffering from polycythemia. Both parents were phenotypically normal and exclusion of paternity has been ruled out by the study of several polymorphic markers located on different chromosomes. The structural modification of Hb Puttelange was established by reversed-phase HPLC analysis of the tryptic digest of the abnormal chain. The amino acid composition of an abnormal βT14 peptide revealed that one of the four residues of Ala was replaced by a Val. Tandem mass spectrometry demonstrated that the substitution concerned position β140 (H18). This hemoglobin displays an increased oxygen affinity that is responsible for the polycythemia. De novo mutations, as demonstrated again in the case of this variant, have the highest probabilities of detection when they lead to pathological manifestations. They may result either from a somatic mutation in a very early stage of the embryological development of the propositus or may have a parental origin with occurrence of a germline mosaicism. The study of the β-globin gene indicated that this case of Hb Puttelange probably arose from a mutation affecting a part of the germline of the father, therefore leading to a true recurrence risk.
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References
Amselem S (1993) Bases moléculaires d'un syndrome génétique de résistance à l'hormone de croissance (syndrome de Laron). Thesis for Graduate at University Paris VII, France
Amselem S, Duquesnoy P, Duriez B, Dastot F, Sobrier ML, Valleix S, Goossens M (1993) Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet 2:355–359
Boerwinkle E, Xiong W, Fourest E, Chan L (1989) Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: application to the apolipoprotein B 3′ hypervariable region. Proc Natl acad Sci USA 86:212–216
Bradley TB, Wohl RC, Petz LD, Perkins HA, Reynolds RD (1980) Possible gonadal mosaicism in a family with hemoglobin Köln. Johns Hopkins Med J 146:236–240
Desmarais E, Vigneron S, Buresi C, Cambien F, Cambou JP, Roizes G (1993) Variant mapping of the Apo(B) AT rich minisatellite. Dependence on nucleotide sequence of the copy number variations. Instability of the non-canonical alleles. Nucleic Acids Res 21:2179–2184
Fanen B, Ghanem N, Vidaud M, Besmond C, Martin J, Costes B, Plassa F, Goossens M (1992) Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics 13:770–776
Ghanem N, Girodon E, Vidaud M, Martin J, Fanen P, Plassa F, Goossens M (1992) A comprehensive scanning method for rapid detection of β-globin gene mutations and polymorphisms. Hum Mutation 1:229–239
Girodon E, Ghanem N, Vidaud M, Riou J, Martin J, Galacteros F, Goossens M (1992) Rapid molecular characterization of mutaleading to unstable hemoglobin β-chain variants. Ann Hematol 65:188–192
Gyllensten UB, Erlich HA (1988) Generation of single-strand DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci USA 85:7652–7656
Hall JG (1988) Somatic mosaicism: observations related to clinical genetics. Am J Hum Genet 43:355–363
Kister J, Poyart C, Edelstein SJ (1987) An expanded two-state allosteric model for interaction of human hemoglobin A with non saturating concentrations of 2,3 diphosphoglycerate. J Biol Chem 262:12085–12091
Lacombe C, Riou J, Godard C, Rosa J, Galacteros F (1986) Characterization approach of “Silent” beta-chain hemoglobin variants. Acta Haematol 78:119–122
Lacombe C, Prome D, Blouquit Y, Bardakdjian, J, Arous N, Bost M, M'rad A, Galacteros F, Prome JC, Rosa J (1990) New results of hemoglobin variant structure determinations by fast atom bombardment mass spectrometry. Hemoglobin 14:529–548
Lalezari I, Lalezari P, Poyart C, Marden M, Kister J, Bohn B, Fermi G, Perutz MF (1990) New effectors of human hemoglobin: structure and function. Biochemistry 29:1515–1523
Myers RM, Maniatis T, Lerman LS (1987) Detection and localization of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol 155:501–527
Nute PE, Stamatoyannopoulos G (1988) Cases of abnormal human hemoglobin produced by de novo mutation. Hemoglobin 12:429–439
Ohba Y, Miyaji T, Murakami M, Kadowaki S, Fujita T, Oimomi M, Hatanaka H, Ishikawa K, Baba S, Hitaka K, Imai K (1986) Hb Himeji or β 140 (H18) Ala→Asp a slightly unstable hemoglobin with increased βN-terminal glycation. Hemoglobin 10:109–126
Orkin SH, Kazazian HH, Antonarakis SE, Goff SC, Boehm CD, Sexton JP, Waber PG, Giardina PJV (1982) Linkage of betathalassemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in the human beta-globin gene cluster. Nature 296:627–631
Rochelte J, Varet B, Boissel JP, Clough K, Labie D, Wajcman H, Bohn B, Magne P, Poyart C (1984) Structure and function of Hb Saint Jacques [α2β2 140(H18) Ala→Thr]: a new high-oxygen-affinity variant with altered biphosphoglycerate binding. Biochim Biophys Acta 785:14–21
Schneider RG, Barwick RC (1986) Electrophoretic mobilities of mutant hemoglobins and mutant globin chains. In CRC handbook series in clinical laboratory science, Section I: Hematology, vol IV. CRC Press, Boca Raton, Florida
Sheffield VC, Cox DR, Lerman LS, Myers RM (1989) Attachment of a 40-base pair G+C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in imroved detection of single-base changes. Proc Natl Acad Sci USA 86:232–236
Wajcman H, Bardakdjian J, Ducrocq R (1993) structural characterization of abnormal hemoglobins from dried blood specimens in a neonatal screening program. Ann Biol Clin 50:867–870
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Wajcman, H., Girodon, E., Promé, D. et al. Germline mosaicism for an alanine to valine substitution at residue β 140 in hemoglobin Puttelange, a new variant with high oxygen affinity. Hum Genet 96, 711–716 (1995). https://doi.org/10.1007/BF00210304
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DOI: https://doi.org/10.1007/BF00210304