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Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease

We describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with...

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Autores principales: Joshi, Mugdha, Anselm, Irina, Shi, Jiahai, Bale, Tejus A., Towne, Meghan, Schmitz-Abe, Klaus, Crowley, Laura, Giani, Felix C., Kazerounian, Shideh, Markianos, Kyriacos, Lidov, Hart G., Folkerth, Rebecca, Sankaran, Vijay G., Agrawal, Pankaj B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853520/
https://www.ncbi.nlm.nih.gov/pubmed/27148589
http://dx.doi.org/10.1101/mcs.a000786
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author Joshi, Mugdha
Anselm, Irina
Shi, Jiahai
Bale, Tejus A.
Towne, Meghan
Schmitz-Abe, Klaus
Crowley, Laura
Giani, Felix C.
Kazerounian, Shideh
Markianos, Kyriacos
Lidov, Hart G.
Folkerth, Rebecca
Sankaran, Vijay G.
Agrawal, Pankaj B.
author_facet Joshi, Mugdha
Anselm, Irina
Shi, Jiahai
Bale, Tejus A.
Towne, Meghan
Schmitz-Abe, Klaus
Crowley, Laura
Giani, Felix C.
Kazerounian, Shideh
Markianos, Kyriacos
Lidov, Hart G.
Folkerth, Rebecca
Sankaran, Vijay G.
Agrawal, Pankaj B.
author_sort Joshi, Mugdha
collection PubMed
description We describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease.
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spelling pubmed-48535202016-05-04 Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease Joshi, Mugdha Anselm, Irina Shi, Jiahai Bale, Tejus A. Towne, Meghan Schmitz-Abe, Klaus Crowley, Laura Giani, Felix C. Kazerounian, Shideh Markianos, Kyriacos Lidov, Hart G. Folkerth, Rebecca Sankaran, Vijay G. Agrawal, Pankaj B. Cold Spring Harb Mol Case Stud Research Article We describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease. Cold Spring Harbor Laboratory Press 2016-05 /pmc/articles/PMC4853520/ /pubmed/27148589 http://dx.doi.org/10.1101/mcs.a000786 Text en © 2016 Joshi et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Article
Joshi, Mugdha
Anselm, Irina
Shi, Jiahai
Bale, Tejus A.
Towne, Meghan
Schmitz-Abe, Klaus
Crowley, Laura
Giani, Felix C.
Kazerounian, Shideh
Markianos, Kyriacos
Lidov, Hart G.
Folkerth, Rebecca
Sankaran, Vijay G.
Agrawal, Pankaj B.
Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease
title Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease
title_full Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease
title_fullStr Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease
title_full_unstemmed Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease
title_short Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease
title_sort mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (pmpca) cause a severe mitochondrial disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853520/
https://www.ncbi.nlm.nih.gov/pubmed/27148589
http://dx.doi.org/10.1101/mcs.a000786
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