Abstract |
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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Authors | Mugdha Joshi, Irina Anselm, Jiahai Shi, Tejus A Bale, Meghan Towne, Klaus Schmitz-Abe, Laura Crowley, Felix C Giani, Shideh Kazerounian, Kyriacos Markianos, Hart G Lidov, Rebecca Folkerth, Vijay G Sankaran, Pankaj B Agrawal |
Journal | Cold Spring Harbor molecular case studies
(Cold Spring Harb Mol Case Stud)
Vol. 2
Issue 3
Pg. a000786
(May 2016)
ISSN: 2373-2873 [Print] United States |
PMID | 27148589
(Publication Type: Journal Article)
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