PUBLICATION
Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome
- Authors
- Melo, U.S., Macedo-Souza, L.I., Figueiredo, T., Muotri, A.R., Gleeson, J.G., Coux, G., Armas, P., Calcaterra, N.B., Kitajima, J.P., Amorim, S., Olávio, T.R., Griesi-Oliveira, K., Coatti, G.C., Rocha, C.R., Martins-Pinheiro, M., Menck, C.F., Zaki, M.S., Kok, F., Zatz, M., Santos, S.
- ID
- ZDB-PUB-150920-5
- Date
- 2015
- Source
- Human molecular genetics 24(24): 6877-85 (Journal)
- Registered Authors
- Calcaterra, Nora
- Keywords
- none
- MeSH Terms
-
- Animals
- Chromosomes, Human, Pair 11
- DNA Mutational Analysis
- Gene Expression*
- Hereditary Sensory and Motor Neuropathy/genetics
- Humans
- Microtubule-Associated Proteins/genetics*
- Optic Atrophies, Hereditary/genetics*
- Sequence Deletion*
- Spastic Paraplegia, Hereditary/genetics*
- Syndrome
- Zebrafish
- Zebrafish Proteins/genetics
- PubMed
- 26385635 Full text @ Hum. Mol. Genet.
Citation
Melo, U.S., Macedo-Souza, L.I., Figueiredo, T., Muotri, A.R., Gleeson, J.G., Coux, G., Armas, P., Calcaterra, N.B., Kitajima, J.P., Amorim, S., Olávio, T.R., Griesi-Oliveira, K., Coatti, G.C., Rocha, C.R., Martins-Pinheiro, M., Menck, C.F., Zaki, M.S., Kok, F., Zatz, M., Santos, S. (2015) Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Human molecular genetics. 24(24):6877-85.
Abstract
SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy. 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 to 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping