LBR – Pelger-Huët Anomaly

Pelger-Huët anomaly (PHA) is a benign autosomal dominant laminopathy characterized by bilobed or unsegmented neutrophil nuclei due to defective chromatin–nuclear membrane interaction. Heterozygous individuals exhibit characteristic hyposegmentation of granulocyte nuclei, while homozygotes may show more pronounced ovoid nuclei and minor skeletal findings. Recognition of PHA on peripheral blood smear serves as a clinical clue for underlying LBR testing and distinguishes it from myelodysplastic and other hematologic disorders (PMID:22338047).

Early linkage and sequencing studies in multiple families established LBR as the PHA gene: two kindreds showed exon 3 c.356C>T (p.Pro119Leu) and IVS11-9A>G splice-site variants, and an isolated patient harbored c.1706C>G (p.Pro569Arg) (PMID:14617022). Subsequent case reports have identified additional missense and frameshift alleles, including c.43C>T (p.Arg15Ter) and c.1757G>A (p.Arg586His) in compound heterozygosity, expanding the allele spectrum (PMID:23824842).

Segregation analysis across at least five families demonstrates co-segregation of LBR variants with hyposegmented nuclei in 19 additional affected relatives, confirming autosomal dominant transmission and high penetrance (PMID:14617022).

The variant spectrum comprises missense changes in the sterol‐reductase domain (e.g., p.Pro569Arg), splicing disruptions (e.g., c.1484-9A>G), and N-terminal truncations (e.g., p.Arg15Ter), with no recurrent founder alleles reported to date. Carrier frequency is unknown but PHA is often incidentally detected in healthy adults.

Functional studies show that heterozygous LBR mutations impair chromatin anchoring without abolishing sterol‐reductase activity. Enzymatic assays in yeast and cell models confirm that PHA‐associated alleles preserve sterol reduction yet disrupt nuclear morphology, separating structural from metabolic functions of LBR (PMID:21327084). Mouse models with N-terminal deletions faithfully recapitulate human PHA without lethal phenotypes, providing in vivo validation.

In summary, definitive genetic and experimental evidence confirms that heterozygous LBR variants cause Pelger-Huët anomaly via disruption of nuclear membrane–chromatin interactions. Laboratory recognition of PHA should prompt targeted LBR sequencing for diagnostic confirmation and familial counseling. Key take-home: PHA is a distinct, nonprogressive blood disorder diagnosable by morphology and molecular testing of LBR.

References

• British journal of haematology • 2003 • Lamin B-receptor mutations in Pelger-Huët anomaly PMID:14617022
• American journal of medical genetics. Part A • 2013 • Pelger-Huet anomaly and a mild skeletal phenotype secondary to mutations in LBR PMID:23824842
• American journal of clinical pathology • 2012 • Understanding and recognizing the Pelger-Huët anomaly PMID:22338047
• Nucleus (Austin, Tex.) • 2010 • Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein PMID:21327084

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