A homozygous lamin B receptor variant resulting in Pelger-Huët anomaly without skeletal dysplasia.

The lamin B receptor (LBR) is an inner nuclear membrane protein with a structural function affecting nuclear segmentation in neutrophils and an enzymatic function as a sterol reductase. Heterozygous LBR variants cause nuclear hyposegmentation (Pelger-Huët anomaly), while homozygous LBR pathogenic variants cause a spectrum of systemic malformations up to severe skeletal deformities and prenatal death. Already in 1981, a homozygous Pelger-Huët proband with ovoid neutrophil nuclei but without special clinical symptoms has been reported. Later it was shown that the amount of LBR was reduced, perhaps due to a regulatory variant. We have now re-analyzed the proband´s DNA and confirmed the existence of a homozygous missense variant (NM_002296.4): c.1445T > G; p.V482G. However, further molecular testing did not reveal any regulatory variant. The missense variant was further investigated: It affects an evolutionary highly conserved amino acid, which is in direct contact with the inner nuclear membrane, but has no direct influence on the LBR sterol reductase activity. A homozygous valine to glycine substitution has not been detected in any study so far. Therefore, we conclude that this variant has a significant effect on the structural function of LBR but no clinically relevant effect on its enzymatic function.