title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
abstract: Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) is a rare mitochondrial disorder that has previously been associated with mutations in PUS1 and YARS2. In the present report, we describe a 6-year old male with an MLASA plus phenotype. This patient had features of MLASA in the setting of developmental delay, sensorineural hearing loss, epilepsy, agenesis of the corpus callosum, failure to thrive, and stroke-like episodes. Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N). Whole exome sequencing did not identify mutations or variants in PUS1 or YARS2 or any known nuclear genes that could affect mitochondrial function and explain this phenotype. Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect. Thus, this mutation in MT-ATP6 may represent the first mtDNA point mutation associated with the MLASA phenotype.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: burrage@bcm.edu.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Burrage
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: stang@ambrygen.com.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: jwang7@bcm.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: donti@bcm.edu.
authors.forename: Taraka R
authors.initials: TR
authors.lastname: Donti
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: Magdalena.Walkiewicz@bcm.edu.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walkiewicz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: jluchak@bcm.edu.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Luchak
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: ziv28@hotmail.com.
authors.forename: Li-Chieh
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: eschmitt@bcm.edu.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Schmitt
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: zniu@bcm.edu.
authors.forename: Zhiyv
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA. Electronic address: rxerana@txch.org.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Erana
authors.affiliation: Department of Radiology, Baylor College of Medicine, Houston, TX, USA. Electronic address: jvhunter@texaschildrens.org.
authors.forename: Jill V
authors.initials: JV
authors.lastname: Hunter
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: bgraham@bcm.edu.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: ljwong@bcm.edu.
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: fscaglia@bcm.edu.
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
mesh_terms: D000140:Acidosis, Lactic / Q000175:diagnosis* / Q000235:genetics; D000595:Amino Acid Sequence; D000756:Anemia, Sideroblastic / Q000175:diagnosis* / Q000235:genetics; D019069:Cell Respiration; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D017240:Mitochondrial Myopathies / Q000175:diagnosis* / Q000235:genetics; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D008969:Molecular Sequence Data; D017354:Point Mutation
chemical_list: D004272:DNA, Mitochondrial; C501005:MT-ATP6 protein, human; D025261:Mitochondrial Proton-Translocating ATPases
keywords: ATP6; Lactic acidosis; MLASA; Mitochondria; Mitochondrial myopathy