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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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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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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DOI: https://doi.org/10.1038/ng925
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