Niemann-Pick type C disease proteins: orphan transporters or membrane rheostats?
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ABSTRACT:
SUBMITTER: Munkacsi AB
PROVIDER: S-EPMC2704495 | biostudies-literature | 2007 Jun
REPOSITORIES: biostudies-literature
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Niemann-Pick type C disease proteins: orphan transporters or membrane rheostats?
Munkacsi Andrew B AB Porto Anthony F AF Sturley Stephen L SL
Future lipidology 20070601 3
Niemann-Pick type C (NPC) disease is a panethnic lysosomal lipidosis, which results in severe cerebellar impairment and death, and is proposed to be a consequence of defective metabolite transport. Numerous models of this disorder have defined the phenotypic impact of misfunction of the NPC proteins, however, their mechanism of action and definition of substrate(s) remain vague and disputed. The proteins may be lipid chaperones, nonspecific transporters, orphan transporters or membrane-sensing r ...[more]
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Project description:OBJECTIVES:The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood. DESIGN:Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients. RESULTS:Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function. CONCLUSIONS:This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.
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Project description:Primary skin fibroblasts from four Niemann-Pick type C patients homozygous for the I1061T mutation and four control individuals were cultured under identical conditions in DMEM containing 10% fetal bovine serum. Cells were harvested at 50-70% confluency. mRNA was isolated with the FastTrack 2.0 mRNA isolation kit according to the manufacturer's instructions (Invitrogen, Carlsbad, CA). A reference RNA comprised of 10 cell lines was used as the control for each hybridized sample (Stratagene, La Jolla, CA). Both sample and reference RNAs were amplified using the MessageAmp II aRNA amplification kit (Ambion, Austin, TX). Set of arrays that are part of repeated experiments Keywords: Biological Replicate
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2007-08-15 | E-GEOD-8770 | biostudies-arrayexpress
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