title: A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression.
abstract: We report a Caucasian boy with intractable epilepsy and global developmental delay. Whole-exome sequencing identified the likely genetic etiology as a novel p.K212E mutation in the X-linked gene HSD17B10 for mitochondrial short-chain dehydrogenase/reductase SDR5C1. Mutations in HSD17B10 cause the HSD10 disease, traditionally classified as a metabolic disorder due to the role of SDR5C1 in fatty and amino acid metabolism. However, SDR5C1 is also an essential subunit of human mitochondrial RNase P, the enzyme responsible for 5'-processing and methylation of purine-9 of mitochondrial tRNAs. Here we show that the p.K212E mutation impairs the SDR5C1-dependent mitochondrial RNase P activities, and suggest that the pathogenicity of p.K212E is due to a general mitochondrial dysfunction caused by reduction in SDR5C1-dependent maturation of mitochondrial tRNAs.
authors.affiliation: a Division of Human Genetics , Department of Pediatrics, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.|b Department of Pediatrics , University of Pennsylvania Perelman School of Medicine , Philadelphia , PA , USA.
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
authors.affiliation: c Center for Personalized Medicine, Children's Hospital Los Angeles , Los Angeles , CA , USA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.affiliation: d Department of Biochemistry and Molecular Biology , Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Megumi
authors.initials: M
authors.lastname: Shigematsu
authors.affiliation: e Center for Anatomy and Cell Biology, Medical University of Vienna , Vienna , Austria.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vilardo
authors.affiliation: d Department of Biochemistry and Molecular Biology , Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Takase
authors.affiliation: a Division of Human Genetics , Department of Pediatrics, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCormick
authors.affiliation: d Department of Biochemistry and Molecular Biology , Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Christian
authors.affiliation: a Division of Human Genetics , Department of Pediatrics, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.|f Massachusetts Eye and Ear Infirmary, Harvard Medical School , Boston , MA , USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Place
authors.affiliation: f Massachusetts Eye and Ear Infirmary, Harvard Medical School , Boston , MA , USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.affiliation: f Massachusetts Eye and Ear Infirmary, Harvard Medical School , Boston , MA , USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Consugar
authors.affiliation: d Department of Biochemistry and Molecular Biology , Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Howard B
authors.initials: HB
authors.lastname: Gamper
authors.affiliation: e Center for Anatomy and Cell Biology, Medical University of Vienna , Vienna , Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Rossmanith
authors.affiliation: d Department of Biochemistry and Molecular Biology , Thomas Jefferson University , Philadelphia , PA , USA.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Hou
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics*; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics*; D000069279:Drug Resistant Epilepsy / Q000235:genetics*; D059472:Exome; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012343:RNA, Transfer / Q000378:metabolism; D043262:Ribonuclease P / Q000378:metabolism*; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D012343:RNA, Transfer; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D043262:Ribonuclease P
keywords: 17β-hydroxysteroid dehydrogenase type 10; HSD10 disease; PRORP; SDR5C1; TRMT10C