Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly).
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.
Hoffmann
Katrin
K
Gene Mapping Center, Max Delbrück Center for Molecular Medicine and Franz Volhard Clinic, HELIOS Klinikum, Charité, Humboldt University, Berlin, Germany.
Dreger
Christine K
CK
Olins
Ada L
AL
Olins
Donald E
DE
Shultz
Leonard D
LD
Lucke
Barbara
B
Karl
Hartmut
H
Kaps
Reinhard
R
Müller
Dietmar
D
Vayá
Amparo
A
Aznar
Justo
J
Ware
Russell E
RE
Sotelo Cruz
Norberto
N
Lindner
Tom H
TH
Herrmann
Harald
H
Reis
André
A
Sperling
Karl
K
D002460:Cell Line; D002878:Chromosomes, Human, Pair 1; D005260:Female; D018703:Founder Effect; D008040:Genetic Linkage; D006098:Granulocytes / Q000473:pathology*; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D010381:Pelger-Huet Anomaly / Q000235:genetics* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D013548:Sweden; D000097682:Lamin B Receptor
D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor