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

• Published in: Nature genetics Vol. 31; no. 4; pp. 410 - 414
• Main Authors: Kaps, Reinhard, Sperling, Karl, Reis, André, Müller, Dietmar, Cruz, Norberto Sotelo, Olins, Donald E, Lucke, Barbara, Karl, Hartmut, Lindner, Tom H, Herrmann, Harald, Olins, Ada L, Ware, Russell E, Hoffmann, Katrin, Aznar, Justo, Vayá, Amparo, Dreger, Christine K, Shultz, Leonard D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2002; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood; Cancer Research; Cell Line; Cell receptors; Chromosome abnormalities; Chromosomes; Chromosomes, Human, Pair 1; Complications and side effects; Diagnosis; Female; Founder Effect; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genes. Genome; Genetic aspects; Genetic Linkage; Genetics; Genomes; Granulocytes; Granulocytes - pathology; Haplotypes; Haplotypes - genetics; Heterozygote; Human Genetics; Humans; Lamin B Receptor; letter; Leukemia; Male; Medical research; Membranes; Microsatellite Repeats; Molecular and cellular biology; Molecular genetics; Morphology; Mortality; Mutation; Neutrophils; Offspring; Pedigree; Pelger-Huet Anomaly - genetics; Pelger-Huet Anomaly - pathology; Physiological aspects; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Risk factors; Sweden; Sweden; Germany; United States > US; Berlin Germany; Maine; Nuclear receptor; Anomaly; Mutation; Gene; Morphology; Granulocyte
• DOI: 10.1038/ng925
• ISSN: 1061-4036

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 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.