title: Mitochondrial tRNA-serine (AGY) m.C12264T mutation causes severe multisystem disease with cataracts.
abstract: Progressive multisystem disease should invoke consideration of potential mitochondrial etiologies. Mitochondrial disease can affect any organ system at any time, particularly involving neurologic, cardiac, muscular, gastroenterologic, and/or ophthalmologic manifestations. We report here a 19-year-old Caucasian man who was followed since birth in multiple pediatric subspecialty clinics for myelomeningocele complications. However, he progressively developed a host of additional problems that were not readily attributable to his neural tube defect involving developmental, ophthalmologic, cardiac, muscular, endocrine, and intermediary metabolic manifestations. Clinical diagnostic testing limited to analysis for common point mutations and deletions in his blood mitochondrial DNA (mtDNA) was not revealing. Skeletal muscle biopsy revealed abnormal mitochondrial morphology and immunostaining, mitochondrial proliferation, and mildly reduced respiratory chain complex I-III activity. Whole mitochondrial genome sequencing analysis in muscle identified an apparently homoplasmic, novel, m.12264C>T transition in the tRNA serine (AGY) gene. The pathogenicity of this mutation was supported by identification of it being present at low heteroplasmy load in his blood (34%) as well as in blood from his maternal grandmother (1%). The proband developed severe nuclear cataracts that proved to be homoplasmic for the pathogenic mtDNA m.12264C>T mutation. This case highlights the value of pursuing whole mitochondrial genome sequencing in symptomatic tissues in the diagnostic evaluation of suspected mitochondrial disease. Furthermore, it is the first report to directly implicate a single mtDNA mutation in the pathogenesis of ocular cataracts and clearly illustrates the important contribution of normal metabolic activity to the function of the ocular lens.
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Schrier
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.forename: Emily
authors.initials: E
authors.lastname: Place
authors.forename: Jack Q
authors.initials: JQ
authors.lastname: Ji
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Golden
authors.forename: Mariarita
authors.initials: M
authors.lastname: Santi
authors.forename: William
authors.initials: W
authors.lastname: Anninger
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
mesh_terms: D000328:Adult; D002386:Cataract / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics*; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D012346:RNA, Transfer, Amino Acyl