Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome

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 pathologyFil: Melo, Uira S.. Universidade de Sao Paulo; BrasilFil: Macedo Souza, Lucia I.. Universidade de Sao Paulo; BrasilFil: Figueiredo, Thalita. Federal University of Paraiba; Brasil. Paraiba State University; BrasilFil: Muotri, Alysson R. University of California at San Diego; Estados UnidosFil: Gleeson, Joseph G.. The Rockefeller University; Estados UnidosFil: Coux, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Armas, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Calcaterra, Nora Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Kitajima, João P.. Mendelics Genomic Analysis; BrasilFil: Amorim, Simone. Universidade de Sao Paulo; BrasilFil: Olávio, Thiago R.. Universidade de Sao Paulo; BrasilFil: Griesi Oliveira, Karina. Universidade de Sao Paulo; BrasilFil: Coatti, Giuliana C.. Universidade de Sao Paulo; BrasilFil: Rocha, Clarissa R.R. Universidade de Sao Paulo; BrasilFil: Martins Pinheiro, Marinalva. Universidade de Sao Paulo; BrasilFil: Menck, Carlos F.M.. Universidade de Sao Paulo; BrasilFil: Zaki, Maha S.. National Research Center. EL Cairo; EgiptoFil: Kok, Fernando. Universidade de Sao Paulo; BrasilFil: Zatz, Mayana. Universidade de Sao Paulo; BrasilFil: Santos, Silvana. Federal University of Paraiba; Brasil. Paraiba State University; Brasi