title: Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease.
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.
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;; Gene Discovery Core, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Mugdha
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Irina
authors.initials: I
authors.lastname: Anselm
authors.affiliation: Whitehead Institute for Biomedical Research, MIT, Cambridge, Massachusetts 02142, USA;; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China;
authors.forename: Jiahai
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Tejus A
authors.initials: TA
authors.lastname: Bale
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;; Gene Discovery Core, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Meghan
authors.initials: M
authors.lastname: Towne
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz-Abe
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;; Gene Discovery Core, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Laura
authors.initials: L
authors.lastname: Crowley
authors.affiliation: Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Felix C
authors.initials: FC
authors.lastname: Giani
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Shideh
authors.initials: S
authors.lastname: Kazerounian
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Markianos
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Hart G
authors.initials: HG
authors.lastname: Lidov
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Folkerth
authors.affiliation: Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;; Gene Discovery Core, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Agrawal
keywords: diffuse cerebellar atrophy; generalized hypotonia due to defect at the neuromuscular junction; hydrocephalus; mitochondrial encephalopathy