Derek E Neilson1, Michael Zech2,3, Robert B Hufnagel1, Jesse Slone1, Xinjian Wang1, Shelli Homan1, Lisa M Gutzwiller4, Elizabeth J Leslie5, Nancy D Leslie1, Jianfeng Xiao6, Peter Hedera7, Mark S LeDoux8, Brian Gebelein4, Friederike Wilbert9, Matthias Eckenweiler9, Juliane Winkelmann2,3,10,11, Donald L Gilbert12, Taosheng Huang1. 1. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 2. Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany. 3. Institute of Human Genetics, Technical University of Munich, Munich, Germany. 4. Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 5. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA. 6. Departments of Neurology and Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, USA. 7. Department of Neurology, University of Louisville, Louisville, Kentucky, USA. 8. Department of Psychology, University of Memphis and Veracity Neuroscience LLC, Memphis, Tennessee, USA. 9. Department of Neuropediatrics and Muscle Disorders, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany. 10. Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany. 11. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany. 12. Division of Neurology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Abstract
BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.
BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.
Authors: Monika B Hartig; Arcangela Iuso; Tobias Haack; Tomasz Kmiec; Elzbieta Jurkiewicz; Katharina Heim; Sigrun Roeber; Victoria Tarabin; Sabrina Dusi; Malgorzata Krajewska-Walasek; Sergiusz Jozwiak; Maja Hempel; Juliane Winkelmann; Matthias Elstner; Konrad Oexle; Thomas Klopstock; Wolfgang Mueller-Felber; Thomas Gasser; Claudia Trenkwalder; Valeria Tiranti; Hans Kretzschmar; Gerd Schmitz; Tim M Strom; Thomas Meitinger; Holger Prokisch Journal: Am J Hum Genet Date: 2011-10-07 Impact factor: 11.025
Authors: Michael Zech; Sylvia Boesch; Esther M Maier; Ingo Borggraefe; Katharina Vill; Franco Laccone; Veronika Pilshofer; Andres Ceballos-Baumann; Bader Alhaddad; Riccardo Berutti; Werner Poewe; Tobias B Haack; Bernhard Haslinger; Tim M Strom; Juliane Winkelmann Journal: Am J Hum Genet Date: 2016-11-10 Impact factor: 11.025
Authors: L De Meirleir; S Seneca; W Lissens; I De Clercq; F Eyskens; E Gerlo; J Smet; R Van Coster Journal: J Med Genet Date: 2004-02 Impact factor: 6.318