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

Nature Genetics volume 31, pages 410–414 (2002)Cite this article

Abstract

Pelger–Huët 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 abnormalities1,2,3. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality4,5. 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 family6, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane7,8. 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 leukemia9, infection10 and toxic drug reactions11, and the evolution of neutrophil nuclear shape12.

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Figure 1: Family pedigrees and characteristics diagnostic of PHA.
Figure 2: Genetic analysis.
Figure 3: Structural and functional organization of the lamin B receptor gene and protein.
Figure 4: Expression of the lamin B receptor in lymphoblastoid cells.
Figure 5: Confocal laser scanning micrographs from normal lymphoblastoid cells and those from individuals with PHA.

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Acknowledgements

We thank all families for their interest and participation; H. Stobbe, R. Witkowski, A. Harder, K. Saar and T.F. Wienker for help in initiating the study; S. Rothe, R. Eckhardt, H. Neitzel, H. Toennies for technical assistance and establishing cell lines; G. Nürnberg and F. Rüschendorf for bioinformatic support; P. Wittig and R. Wolf for preparing blood smears; and F.C. Luft, P. Nürnberg and P. Lichter for support. This work has been supported by a grant from the Deutsche Forschungsgemeinschaft and from the US National Institutes of Health. A.L.O. and D.E.O. were supported by grants from the German Cancer Research Center and from the Davis Family Foundation.

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Authors and Affiliations

  1. Gene Mapping Center, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin, D 13125, Germany

    Katrin Hoffmann, Barbara Lucke & André Reis

  2. Franz Volhard Clinic, HELIOS Klinikum, Charité, Humboldt University, Berlin, Germany

    Katrin Hoffmann

  3. German Cancer Research Center, Heidelberg, Germany

    Christine K. Dreger & Harald Herrmann

  4. Foundation for Blood Research, Scarborough, Maine and new address Bowdoin College, Brunswick, Maine, USA

    Ada L. Olins & Donald E. Olins

  5. The Jackson Laboratory, Bar Harbor, Maine, USA

    Leonard D. Shultz

  6. Gelenau, Germany

    Hartmut Karl

  7. Institute of Transfusion Medicine, DRK, Chemnitz, Germany

    Reinhard Kaps

  8. Institute of Medical Genetics, Klinikum Chemnitz, Chemnitz, Germany

    Dietmar Müller

  9. Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain

    Amparo Vayá & Justo Aznar

  10. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA

    Russell E. Ware

  11. Hospital Infantil del Estado de Sonora, Hermosillo, Mexico

    Norberto Sotelo Cruz

  12. Department of Nephrology, Medical University Clinic, Würzburg, Germany

    Tom H. Lindner

  13. Institute of Human Genetics, University of Erlangen–Nürnberg, Erlangen, Germany

    André Reis

  14. Institute of Human Genetics, Charité, Humboldt University, Augustenburger Platz 1, Berlin, D 13353, Germany

    Karl Sperling

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Correspondence to Karl Sperling.

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Hoffmann, K., Dreger, C., Olins, A. et al. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huët anomaly). Nat Genet 31, 410–414 (2002). https://doi.org/10.1038/ng925

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