Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2

Abstract

This is the first description of slowly progressive Niemann-Pick disease type C (NPC) without the typical lysosomal storage in bone marrow and viscera in two descendants of a group of 17th century French-Canadians. The index patient was a married 43-year-old woman with onset of dementia in her thirties, later followed by the development of ataxia and athetoid movements. Her autopsy disclosed frontal lobe atrophy, neurolysosomal storage with oligolamellar inclusion and tau-positive neurofibrillary tangles. Of the 119 family members screened, only a married 42-year-old sister displayed symptoms of a dementia. Both women displayed vertical supranuclear ophthalmoplegia; expressive aphasia; concrete, stimulus-bound, perseverative behavior; and impaired conceptualization and planning. Cultured fibroblasts showed decreased cholesterol esterification and positive filipin staining, but no mutation was detected in coding or promoter regions of the NPC1 gene using conformation sensitive gel electrophoresis and sequencing. Sequencing showed a homozygous gene mutation that is predicted to result in an amino acid substitution, V39M, in the cholesterol binding protein HE1 (NPC2). Adult-onset NPC2 with lysosomal storage virtually restricted to neurons represents a novel phenotypic and genotypic variant with diffuse cognitive impairment and focal frontal involvement described for the first time.

Structure of a cholesterol-binding protein deficient in Niemann–Pick type C2 disease

“…Other structure͞function relationships from genetic analysis of NP-C2 patients are limited, as most mutations cause severe truncation of the protein (26). Recently, a substitution of methionine for Val-20 has been reported in a patient with late-onset NP-C2 (27). Our model predicts that this substitution would affect cholesterol binding as Val-20 lies at the top of the proposed sterol-binding site (Fig.…”

Saccharomyces cerevisiae Npc2p Is a Functionally Conserved Homologue of the Human Niemann-Pick Disease Type C 2 Protein, hNPC2

“…When folded onto the bNPC2 structure, the scNpc2p sequence fits well into seven beta strands (A to G) arranged into two opposing sheets. We find that the majority of amino acids that are mutated in the NP-C patient (25,33,34,36) are denoted with a star. The ML domains of hNPC2, bNPC2, and scNpc2p, which span amino acids 24 to 145, 24 to 145, and 44 to 168, respectively, are highlighted in gray (amino acid numbering includes signal peptide; cleavage sites denoted with arrows).…”

Subcortical Volumetric Reductions in Adult Niemann-Pick Disease Type C: A Cross-Sectional Study

“…Cognitive impairment is a core symptom cluster in adult NPC, in addition to movement disturbance, gaze palsy, and psychiatric illness, 2,3 and is present, to some degree, in all adult patients at diagnosis and progresses with time. 2 Significant memory and executive impairment have been described in a number of adult patients in case reports 2,3,14,25 ; however, few studies have systematically examined cognitive function in adult patients with NPC. Klarner et al 26 demonstrated that verbal memory impairment was present in most adult patients with moderate progression, whereas executive impairment occurred early.…”