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

Hum Mol Genet. 2015 Dec 15;24(24):6877-85. doi: 10.1093/hmg/ddv388.

Uirá S Melo ¹, Lucia I Macedo-Souza ¹, Thalita Figueiredo ², Alysson R Muotri ³, Joseph G Gleeson ⁴, Gabriela Coux ⁵, Pablo Armas ⁵, Nora B Calcaterra ⁵, João P Kitajima ⁶, Simone Amorim ⁷, Thiago R Olávio ¹, Karina Griesi-Oliveira ¹, Giuliana C Coatti ¹, Clarissa R R Rocha ⁸, Marinalva Martins-Pinheiro ⁸, Carlos F M Menck ⁸, Maha S Zaki ⁹, Fernando Kok ¹⁰, Mayana Zatz ¹¹, Silvana Santos ²

Affiliations

1 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.
2 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.
3 Department of Pediatrics/Rady Children's Hospital San Diego, University of California San Diego, La Jolla, CA 92093, USA.
4 Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065, USA.
5 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.
6 Mendelics Genomic Analysis, São Paulo, SP 04013-000, Brazil.
7 Department of Neurology, School of Medicine, University of Sao Paulo (USP), São Paulo, SP 01246-903, Brazil.
8 Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP 05508-900, Brazil and.
9 Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
10 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.
11 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, [email protected].

PMID: 26385635 DOI: 10.1093/hmg/ddv388

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.

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