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- Title
Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger?Huët anomaly).
- Authors
Hoffmann, Katrin; Dreger, Christine K.; Olins, Ada L.; Olins, Donald E.; Shultz, Leonard D.; Lucke, Barbara; Karl, Hartmut; Kaps, Reinhard; Müller, Dietmar; Vayá, Amparo; Aznar, Justo; Ware, Russell E.; Cruz, Norberto Sotelo; Lindner, Tom H.; Herrmann, Harald; Reis, André; Sperling, Karl
- Abstract
Pelger-Huët anomaly (PHA; OMIM [sup *]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[sup 1-3]. Homozygous off-spring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and post-natal mortality[sup 4,5]. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome lq41-43. 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[sup 6], is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane[sup 7,8]. 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 dosedependent manner. Our findings have implications for understanding nuclear envelopeheterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia[sup 9], infection[sup 10] and toxic drug reactions[sup 11], and the evolution of neutrophil nuclear shape[sup 12].
- Subjects
CHROMATIN; GRANULOCYTES; GENETIC mutation; GENETICS
- Publication
Nature Genetics, 2002, Vol 31, Issue 4, p410
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng925