Whole-Exome Sequencing Study of Fibroblasts Derived From Patients With Cerebellar Ataxia Referred to Investigate CoQ10 Deficiency.

Autor: Monfrini E; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Pesini A; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Biella F; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Sobreira CFR; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Emmanuele V; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Brescia G; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Lopez LC; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Tadesse S; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Hirano M; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Comi GP; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Quinzii CM; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain., Di Fonzo A; Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico (E.M., G.B., A.D.F.), Neurology Unit, Milan, Italy; Dino Ferrari Center (E.M., F.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Italy; Department of Neurology (A.P., V.E., S.T., M.H., C.M.Q.), Columbia University Medical Center, New York; Universidade de São Paulo (C.F.R.S.), Ribeirão Preto Medical School, Department of Neurosciences, Brazil; Departamento de Fisiología (L.C.L.), Facultad de Medicina, Universidad de Granada, Spain; and Centro de Investigación Biomédica (L.C.L.), Instituto de Biotecnología, Universidad de Granada, Spain.
Jazyk: angličtina
Zdroj: Neurology. Genetics [Neurol Genet] 2023 Mar 14; Vol. 9 (2), pp. e200058. Date of Electronic Publication: 2023 Mar 14 (Print Publication: 2023).
DOI: 10.1212/NXG.0000000000200058
Abstrakt: Background and Objectives: Coenzyme Q 10 (CoQ 10 )-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ 10 biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ 10 supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ 10 levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ 10 deficiency.
Methods: WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ 10 deficiency and/or cerebellar ataxia. CoQ 10 levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts.
Results: A definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genes COQ8A ( ADCK3 ) (n = 3 samples), ATP1A3 (n = 2), PLA2G6 (n = 1), SPG7 (n = 1), and MFSD8 (n = 1). Five novel mutations were found ( COQ8A n = 3, PLA2G6 n = 1, and MFSD8 n = 1). CoQ 10 levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygous COQ8A pathogenic variants, 1 harboring a homozygous pathogenic SPG7 variant, and 1 with an unknown molecular defect.
Discussion: This work confirms the importance of COQ8A gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ 10 deficiency and suggests SPG7 mutations as a novel cause of secondary CoQ 10 deficiency.
(Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Databáze: MEDLINE
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