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Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly)

Official URL:https://doi.org/10.1038/ng925
PubMed:View item in PubMed
Creators Name:Hoffmann, K. and Dreger, C.K. and Olins, A.L. and Olins, D.E. and Shultz, L.D. and Lucke, B. and Karl, H. and Kaps, R. and Mueller, D. and Vaya, A. and Aznar, J. and Ware, R.E. and Cruz, N.S. and Lindner, T.H. and Herrmann, H. and Reis, A. and Sperling, K.
Journal Title:Nature Genetics
Journal Abbreviation:Nat Genet
Volume:31
Number:4
Page Range:410-414
Date:August 2002
Keywords:Cell Line, Cytoplasmic and Nuclear Receptors, Founder Effect, Genetic Linkage, Granulocytes, Haplotypes, Heterozygote, Human Pair 1 Chromosomes, Microsatellite Repeats, Mutation, Pedigree, Pelger-Huet Anomaly, Sweden
Abstract:Pelger-Huet anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape.
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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