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Rare Dis. 2016 Sep 27;4(1):e1241363. eCollection 2016.

Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism.

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Department of Molecular Biophysics & Biochemistry, Yale University , New Haven, CT, USA.
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA; Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA.


Lamin B Receptor (LBR) is an inner nuclear membrane protein associated with the rare human diseases Pelger-Huët anomaly and Greenberg skeletal dysplasia. A new study has used CRISPR/Cas9-mediated genetic manipulations in a human cell system to determine that the molecular etiology of these previously poorly understood disorders is a defect in cholesterol synthesis due to loss of LBR-associated sterol C14 reductase activity. The study furthermore determined that disease-associated LBR point mutations reduce sterol C14 reductase activity by decreasing the affinity of LBR for the reducing agent NADPH. Moreover, two disease-associated LBR truncation mutants were found to be highly unstable at the protein level and are rapidly turned over by a novel nuclear membrane-based protein quality control pathway. Thus, truncated LBR variants can now be used as model substrates for further investigations of nuclear protein quality control to uncover possible implications for other disease-associated nuclear envelopathies.


ERAD; Greenberg skeletal dysplasia; Pelger-Huët anomaly; laminopathy; nuclear envelope; proteasome; protein quality control; sterol C14 reductase; sterol metabolism; ubiquitin

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