Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly

Abstract

The nature of the wild-type gene product at the mouse ichthyosis (ic) locus has been of great interest because mutations at this locus cause marked abnormalities in nuclear heterochromatin, similar to those observed in Pelger-Huët anomaly (PHA). We recently found that human PHA is caused by mutations in the gene (LBR) encoding lamin B receptor, an evolutionarily conserved inner nuclear membrane protein involved in nuclear assembly and chromatin binding. Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype similar to PHA, and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. In this study, we identified one nonsense (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus. These allelic mutations are predicted to result in truncated or severely impaired LBR protein. Our studies of mice homozygous for the ic(J) mutation revealed a complete loss of LBR protein as shown by immunofluorescence microscopy and immunoblotting. The findings provide the molecular basis for the heterochromatin clumping and other distinct phenotypes caused by ic mutations. These spontaneous Lbr mutations confirm the molecular basis of human PHA and provide a small animal model for determination of the precise function of LBR in normal and pathological states.

An Absence of Nuclear Lamins in Keratinocytes Leads to Ichthyosis, Defective Epidermal Barrier Function, and Intrusion of Nuclear Membranes and Endoplasmic Reticulum into the Nuclear Chromatin

“…In contemplating the skin pathology in our mice, we were intrigued by the fact that a deficiency of the lamin B receptor (LBR) causes ichthyosis (35). The amino-terminal domain of LBR binds to B-type lamins, while the carboxyl terminus contains a sterol ⌬ 14 -reductase domain.…”

“…A deficiency of the lamin B receptor (LBR) also causes ichthyosis (35). The N-terminal domain of LBR binds to B-type lamins, while the C terminus has sterol ⌬ 14 -reductase activity.…”

Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing

“…These homozygous mutant mice are born at a ~50% reduced frequency from the expected Mendelian ratio (36), demonstrating that LBR knockout leads to an embryonic defect. Yet, the sex distributions of live births were not reported and so it is unknown if there is a sex bias or simply ~50% penetrance of the lethality phenotype that is evenly distributed between the two sexes.…”

Pelger-Huët Anomaly: A Critical Review of the Literature

“…The ic locus on mouse chromosome 1 shares conserved synteny with the human LBR locus on human chromosome 1. In 2003, Shultz et al [15] demonstrated that mutations in both alleles of the mouse homologue LBR cause autosomal recessive ichthyosis in mice, a disorder in which nuclear morphology is very similar to that in PHA homozygosity. Mice homozygous for the ichthyosis mutation provide a single gene model for determination of the precise function of LBR in normal and pathological states [15].…”

“…In 2003, Shultz et al [15] demonstrated that mutations in both alleles of the mouse homologue LBR cause autosomal recessive ichthyosis in mice, a disorder in which nuclear morphology is very similar to that in PHA homozygosity. Mice homozygous for the ichthyosis mutation provide a single gene model for determination of the precise function of LBR in normal and pathological states [15]. Until now, 11 different LBR mutations have been detected as the molecular basis of human PHA [11].…”