title: Linkage analysis of the hemoglobin F determinant(s) in an Australian hemoglobin Lepore (Boston) kindred.
abstract: Genetic determinants that influence the levels of fetal hemoglobin (Hb F) in a single Australian kindred with heterozygous Hb Lepore (Boston) were sought. There were 22 affected individuals, some of whom had high Hb F and others with Hb F levels within the normal range. Family members were typed for restriction fragment length polymorphisms (RFLPs) associated with the beta-globin gene complex and the nearby genetic markers D11S12, INS, HRAS, and PTH. Prior to linkage analysis, a cohort of 54 unrelated Hb Lepore heterozygotes was analyzed to establish the distribution of Hb F levels measured by alkaline denaturation (Hb FAD). An Hb F level of > 2.0% was used as the cutoff point for linkage analysis of the putative hereditary persistence of fetal hemoglobin (HPFH) determinant(s) in this kindred. Positive peak lod scores were obtained for the entire pedigree between the HPFH determinant and Hb Lepore (Zm+f = 2.35 at theta = 0.15) and beta-globin cluster (HBBC) (Zm+f = 2.38 at theta = 0.20) marker loci, indicating the possibility of an independent HPFH gene at some distance from the beta-globin gene cluster. However, most of these lod scores result from the non-Hb Lepore members of the family who, with one exception, do not have high Hb F, and when only those affected with Hb Lepore were analyzed the lod score values at these loci fell to small positive values (< 1.0). These data do not support an independent cosegregating HPFH determinant separate from the Hb Lepore locus in this pedigree. The results favor a pleiotropic effect of the Hb Lepore lesion itself influencing Hb F levels by genetic or environmental factors not yet elucidated.
authors.affiliation: Department of Molecular Genetics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: P I
authors.initials: PI
authors.lastname: Motum
authors.forename: J A
authors.initials: JA
authors.lastname: Donald
authors.forename: R J
authors.initials: RJ
authors.lastname: Trent
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002648:Child; D002675:Child, Preschool; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis / Q000235:genetics*; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D005819:Genetic Markers; D005914:Globins / Q000235:genetics; D006453:Hemoglobinopathies / Q000235:genetics; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D005819:Genetic Markers; D006455:Hemoglobins, Abnormal; D005914:Globins; D005319:Fetal Hemoglobin; C037659:hemoglobin Lepore