Identification of <i>HE1</i> as the Second Gene of Niemann-Pick C Disease

TLDR

Niemann‑Pick type C2 disease (NP‑C2) is a fatal hereditary disorder of unknown etiology characterized by defective egress of cholesterol from lysosomes. The authors treated NP‑C2 fibroblasts with exogenous recombinant HE1 protein, which reduced lysosomal accumulation of LDL‑derived cholesterol. The study demonstrates that NP‑C2 is caused by loss of the lysosomal protein HE1, with HE1 absent in patient fibroblasts, mutations identified in the HE1 gene, and recombinant HE1 protein rescuing cholesterol accumulation.

Abstract

Niemann-Pick type C2 disease (NP-C2) is a fatal hereditary disorder of unknown etiology characterized by defective egress of cholesterol from lysosomes. Here we show that the disease is caused by a deficiency in HE1, a ubiquitously expressed lysosomal protein identified previously as a cholesterol-binding protein. HE1 was undetectable in fibroblasts from NP-C2 patients but present in fibroblasts from unaffected controls and NP-C1 patients. Mutations in the HE1 gene, which maps to chromosome 14q24.3, were found in NP-C2 patients but not in controls. Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein–derived cholesterol.