LBR – Greenberg Dysplasia

Greenberg skeletal dysplasia is a perinatal lethal autosomal recessive chondrodystrophy characterized by severe hydrops fetalis and short, bowed long bones with abnormal chondro-osseous calcification. Pathogenic biallelic variants in LBR disrupt the sterol C14-reductase activity of the inner nuclear membrane protein, leading to accumulation of cholesta-8,14-dien-3β-ol and intrauterine lethality. The disorder follows a clear autosomal recessive inheritance pattern with heterozygous carriers typically asymptomatic or exhibiting benign Pelger-Huët anomaly.

Genetic evidence includes at least eight unrelated probands from five families harboring homozygous or compound heterozygous loss-of-function and missense variants such as c.1379A>G (p.Asp460Gly), identified in two fetuses from a consanguineous family (PMID:30561119). Additional reports include a homozygous exon 13 indel causing protein truncation in an HEM case (PMID:12618959), and multiple frameshift and splice-site mutations segregating with disease.

A clear genotype–phenotype correlation emerges: truncating variants abolish sterol reductase function and cause lethal Greenberg dysplasia, whereas heterozygous or hypomorphic missense alleles may underlie mild skeletal anomalies or Pelger-Huët anomaly. The variant spectrum encompasses frameshifts (e.g., c.638dup (p.Gly214fs)), splice-site, and key missense changes in the sterol reductase domain.

Functional assays strongly support a loss-of-function mechanism: patient fibroblasts and yeast complementation studies demonstrate failure of mutant LBR to rescue C14-reductase deficiency (PMID:21327084); CRISPR/Cas9 knockouts confirm essentiality for cholesterol synthesis; and mouse embryo expression mirrors human skeletal involvement. Metabolite profiling consistently reveals elevated cholesta-8,14-dien-3β-ol.

Mechanistic studies separate LBR’s dual functions, showing that sterol reductase activity is indispensable for intrauterine development, while structural roles in chromatin tethering underlie Pelger-Huët anomaly. Mutant proteins display reduced NADPH affinity or enhanced proteasomal degradation, underscoring enzyme instability.

In summary, robust genetic and experimental data establish a strong association between LBR and Greenberg dysplasia. Clinically, genetic testing of LBR in fetuses with nonimmune hydrops and skeletal dysplasia enables definitive diagnosis and informs prenatal counseling. Key take-home: Biallelic LBR variants causing loss of sterol C14-reductase activity are diagnostic of Greenberg skeletal dysplasia.

References

• American journal of human genetics • 2003 • Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene. PMID:12618959
• 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
• Rare diseases (Austin, Tex.) • 2016 • Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism. PMID:27830109

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