title: Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome.
abstract: SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy (SPOAN). Affected patients are wheelchair bound after 15 years old, with progressive joint contractures and spine deformities. SPOAN patients also have sub normal vision secondary to apparently non-progressive congenital optic atrophy. A potential causative gene was mapped at 11q13 ten years ago. Here we performed next-generation sequencing in SPOAN-derived samples. While whole-exome sequencing failed to identify the causative mutation, whole-genome sequencing allowed to detect a homozygous 216-bp deletion (chr11.hg19:g.66,024,557_66,024,773del) located at the non-coding upstream region of the KLC2 gene. Expression assays performed with patient's fibroblasts and motor neurons derived from SPOAN patients showed KLC2 overexpression. Luciferase assay in constructs with 216-bp deletion confirmed the overexpression of gene reporter, varying from 48 to 74%, as compared with wild-type. Knockdown and overexpression of klc2 in Danio rerio revealed mild to severe curly-tail phenotype, which is suggestive of a neuromuscular disorder. Overexpression of a gene caused by a small deletion in the non-coding region is a novel mechanism, which to the best of our knowledge, was never reported before in a recessive condition. Although the molecular mechanism of KLC2 up-regulation still remains to be uncovered, such example adds to the importance of non-coding regions in human pathology.
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP 05508-090, Brazil.
authors.forename: Uirá S
authors.initials: US
authors.lastname: Melo
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP 05508-090, Brazil.
authors.forename: Lucia I
authors.initials: LI
authors.lastname: Macedo-Souza
authors.affiliation: Northeast Biotechnology Network (RENORBIO), Federal University of Paraiba (UFPB), Joao Pessoa, PB 58051-900, Brazil, Department of Biology, Paraiba State University (UEPB), Campina Grande, PB 58429-500, Brazil.
authors.forename: Thalita
authors.initials: T
authors.lastname: Figueiredo
authors.affiliation: Department of Pediatrics/Rady Children's Hospital San Diego, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.affiliation: Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Rosario, SF S2002LRK, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Coux
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Rosario, SF S2002LRK, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Armas
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR), Rosario, SF S2002LRK, Argentina.
authors.forename: Nora B
authors.initials: NB
authors.lastname: Calcaterra
authors.affiliation: Mendelics Genomic Analysis, São Paulo, SP 04013-000, Brazil.
authors.forename: João P
authors.initials: JP
authors.lastname: Kitajima
authors.affiliation: Department of Neurology, School of Medicine, University of Sao Paulo (USP), São Paulo, SP 01246-903, Brazil.
authors.forename: Simone
authors.initials: S
authors.lastname: Amorim
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP 05508-090, Brazil.
authors.forename: Thiago R
authors.initials: TR
authors.lastname: Olávio
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP 05508-090, Brazil.
authors.forename: Karina
authors.initials: K
authors.lastname: Griesi-Oliveira
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP 05508-090, Brazil.
authors.forename: Giuliana C
authors.initials: GC
authors.lastname: Coatti
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP 05508-900, Brazil and.
authors.forename: Clarissa R R
authors.initials: CR
authors.lastname: Rocha
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP 05508-900, Brazil and.
authors.forename: Marinalva
authors.initials: M
authors.lastname: Martins-Pinheiro
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP 05508-900, Brazil and.
authors.forename: Carlos F M
authors.initials: CF
authors.lastname: Menck
authors.affiliation: Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP 05508-090, Brazil, Mendelics Genomic Analysis, São Paulo, SP 04013-000, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.affiliation: Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP 05508-090, Brazil, mayazatz@usp.br.
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.affiliation: Northeast Biotechnology Network (RENORBIO), Federal University of Paraiba (UFPB), Joao Pessoa, PB 58051-900, Brazil, Department of Biology, Paraiba State University (UEPB), Campina Grande, PB 58429-500, Brazil.
authors.forename: Silvana
authors.initials: S
authors.lastname: Santos
mesh_terms: D000818:Animals; D002880:Chromosomes, Human, Pair 11; D004252:DNA Mutational Analysis; D015870:Gene Expression; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics; D006801:Humans; D016547:Kinesins; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000235:genetics*; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D013577:Syndrome; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D008869:Microtubule-Associated Proteins; D029961:Zebrafish Proteins; D016547:Kinesins