title: Dosage effect of zero to three functional LBR-genes in vivo and in vitro.
abstract: The Lamin B receptor (LBR) is a pivotal architectural protein in the nuclear envelope. Mutations in the Lamin B receptor lead to nuclear hyposegmentation (Pelger-Huët anomaly). We have exactly quantified the nuclear lobulation in neutrophils from individuals with 0, 1, 2 and 3 functional copies of the lamin B receptor gene and analyzed the effect of different mutation types. Our data demonstrate that there is a highly significant gene-dosage effect between the gene copy number and the nuclear segmentation index of neutrophils. This finding is paralleled by a dose-dependent increase in LBR protein and staining intensity of the nuclear membrane in corresponding lymphoblastoid cell lines, which demonstrates a significant correlation on the protein level as well. We further show that LBR expression continually increases during granulopoiesis in vitro from human precursor cells with ovoid nuclei to multi-segmented neutrophil nuclei 11 days later, indicating relevance for regular human granulopoiesis. Altogether, LBR is a unique model that will allow the systematic study of gene-dosage effects and of modifying endogeneous and exogeneous factors on granulopoiesis.
authors.affiliation: Institute of Medical Genetics, Charité University Medicine, Berlin, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Gravemann
authors.forename: Nele
authors.initials: N
authors.lastname: Schnipper
authors.forename: Hannes
authors.initials: H
authors.lastname: Meyer
authors.forename: Amparo
authors.initials: A
authors.lastname: Vaya
authors.forename: Malgorzata Jm
authors.initials: MJ
authors.lastname: Nowaczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Rajab
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Bastian
authors.initials: B
authors.lastname: Salewsky
authors.forename: Holger
authors.initials: H
authors.lastname: Tönnies
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
authors.forename: Hans H
authors.initials: HH
authors.lastname: Stassen
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D018628:Gene Dosage; D005786:Gene Expression Regulation; D006801:Humans; D019891:Leukopoiesis / Q000235:genetics; D009154:Mutation; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D000097682:Lamin B Receptor
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor