LBR – LBR-related Regressive Spondylometaphyseal Dysplasia

The lamin-B receptor (LBR) encodes a dual-function inner nuclear membrane protein with both sterol C14-reductase activity and chromatin-anchoring roles. Pathogenic biallelic variants in LBR underlie a spectrum of phenotypes, including Pelger–Huët anomaly, Greenberg dysplasia, and the regressive type of spondylometaphyseal dysplasia (LBR-R-SMD). LBR-R-SMD presents prenatally with shortened and bowed tubular bones, metaphyseal irregularities, and a narrow thorax, often leading to perinatal lethality or severe skeletal malformations.

Autosomal recessive inheritance is established by a pseudodominant pedigree in which a fetus and his affected father both harbor homozygous c.1534C>T (p.Arg512Trp) (PMID:34467646), and a consanguineous Moroccan family with two affected fetuses carrying homozygous c.1379A>G (p.Asp460Gly) (PMID:30561119).

Across these two families, there are 3 probands and 1 additional affected relative demonstrating segregation of homozygous missense variants in LBR (PMID:34467646; PMID:30561119). The variant spectrum for LBR-R-SMD includes missense alleles within the sterol reductase domain such as c.1534C>T (p.Arg512Trp) and c.1379A>G (p.Asp460Gly).

Functional assays show that LBR missense mutations abolish sterol C14-reductase activity: patient-derived alleles fail to rescue C14-reductase deficient yeast and human cell models, confirming an enzymatic loss-of-function mechanism distinct from structural chromatin interactions (PMID:21327084). Carrier parents lack Pelger anomaly, indicating selective impairment of sterol reductase function.

Cellular and animal studies corroborate pathogenicity: LBR truncations and point mutants yield cholesterol auxotrophy in human cell lines, reduced protein stability at the nuclear envelope, and embryonic expression in skeletal precursors mirroring sites of dysplasia in mouse models (PMID:27336722).

No conflicting evidence has been reported for LBR in regressive spondylometaphyseal dysplasia. The genetic and experimental data integrate to support a loss-of-function mechanism via sterol reductase deficiency, accounting for the prenatal skeletal phenotype.

Key Take-home: Biallelic LBR variants cause autosomal recessive regressive spondylometaphyseal dysplasia through loss of sterol reductase activity, enabling accurate prenatal diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2022 • Antenatal diagnostic dilemma in a pseudodominant pedigree with lamin-B receptor (LBR)-related regressive spondylometaphyseal dysplasia. PMID:34467646
• American journal of medical genetics. Part A • 2019 • A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes. PMID:30561119
• Nucleus (Austin, Tex.) • 2010 • Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. PMID:21327084
• eLife • 2016 • The Lamin B receptor is essential for cholesterol synthesis and perturbed by disease-causing mutations. PMID:27336722

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