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Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance

In Npc1 null mice, a model for Niemann Pick Disease Type C1, it has been reported that hepatocyte insulin receptor function is significantly impaired, consistent with growing evidence that membrane fluidity and microdomain structure have an important role in insulin signal transduction. However, whe...

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Autores principales: Kirk, J., Porter, K. M., Parker, V., Barroso, I., O’Rahilly, S., Hendriksz, C., Semple, R. K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757264/
https://www.ncbi.nlm.nih.gov/pubmed/20521171
http://dx.doi.org/10.1007/s10545-010-9107-5
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author Kirk, J.
Porter, K. M.
Parker, V.
Barroso, I.
O’Rahilly, S.
Hendriksz, C.
Semple, R. K.
author_facet Kirk, J.
Porter, K. M.
Parker, V.
Barroso, I.
O’Rahilly, S.
Hendriksz, C.
Semple, R. K.
author_sort Kirk, J.
collection PubMed
description In Npc1 null mice, a model for Niemann Pick Disease Type C1, it has been reported that hepatocyte insulin receptor function is significantly impaired, consistent with growing evidence that membrane fluidity and microdomain structure have an important role in insulin signal transduction. However, whether insulin receptor function is also compromised in human Niemann Pick disease Type C1 is unclear. We now report a girl who developed progressive dementia, ataxia and opthalmoplegia from 9 years old, followed by severe acanthosis nigricans, hirsutism and acne at 11 years old. She was diagnosed with Niemann Pick Disease type C1 (OMIM#257220) based on positive filipin staining and reduced cholesterol-esterifying activity in dermal fibroblasts, and homozygosity for the p.Ile1061Thr NPC1 mutation. Further analysis revealed her also to be heterozygous for a novel trinucleotide deletion (c.3659 + 1_3659 + 3delGTG) at the end of exon 20 of INSR, encoding the insulin receptor, leading to deletion of Trp1193 in the intracellular tyrosine kinase domain. INSR mRNA and protein levels were normal in dermal fibroblasts, consistent with a primary signal transduction defect in the mutant receptor. Although the proband was significantly more insulin resistant than her father, who carried the INSR mutation but was only heterozygous for the NPC1 variant, their respective degrees of IR were very similar to those previously reported in a father–daughter pair with the closely related p.Trp1193Leu INSR mutation. This suggests that loss of NPC1 function, with attendant changes in membrane cholesterol composition, does not significantly modify the IR phenotype, even in the context of severely impaired INSR function.
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spelling pubmed-37572642013-09-04 Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance Kirk, J. Porter, K. M. Parker, V. Barroso, I. O’Rahilly, S. Hendriksz, C. Semple, R. K. J Inherit Metab Dis Case Report In Npc1 null mice, a model for Niemann Pick Disease Type C1, it has been reported that hepatocyte insulin receptor function is significantly impaired, consistent with growing evidence that membrane fluidity and microdomain structure have an important role in insulin signal transduction. However, whether insulin receptor function is also compromised in human Niemann Pick disease Type C1 is unclear. We now report a girl who developed progressive dementia, ataxia and opthalmoplegia from 9 years old, followed by severe acanthosis nigricans, hirsutism and acne at 11 years old. She was diagnosed with Niemann Pick Disease type C1 (OMIM#257220) based on positive filipin staining and reduced cholesterol-esterifying activity in dermal fibroblasts, and homozygosity for the p.Ile1061Thr NPC1 mutation. Further analysis revealed her also to be heterozygous for a novel trinucleotide deletion (c.3659 + 1_3659 + 3delGTG) at the end of exon 20 of INSR, encoding the insulin receptor, leading to deletion of Trp1193 in the intracellular tyrosine kinase domain. INSR mRNA and protein levels were normal in dermal fibroblasts, consistent with a primary signal transduction defect in the mutant receptor. Although the proband was significantly more insulin resistant than her father, who carried the INSR mutation but was only heterozygous for the NPC1 variant, their respective degrees of IR were very similar to those previously reported in a father–daughter pair with the closely related p.Trp1193Leu INSR mutation. This suggests that loss of NPC1 function, with attendant changes in membrane cholesterol composition, does not significantly modify the IR phenotype, even in the context of severely impaired INSR function. Springer Netherlands 2010-06-03 2010 /pmc/articles/PMC3757264/ /pubmed/20521171 http://dx.doi.org/10.1007/s10545-010-9107-5 Text en © The Author(s) 2010
spellingShingle Case Report
Kirk, J.
Porter, K. M.
Parker, V.
Barroso, I.
O’Rahilly, S.
Hendriksz, C.
Semple, R. K.
Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance
title Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance
title_full Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance
title_fullStr Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance
title_full_unstemmed Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance
title_short Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance
title_sort loss of npc1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757264/
https://www.ncbi.nlm.nih.gov/pubmed/20521171
http://dx.doi.org/10.1007/s10545-010-9107-5
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