Overexpression ofKLC2due 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.

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

“…The specific role of kinesin-1 in this process is likely derived from its preference for microtubules enriched in acetylated and GTP-bound tubulin (51,54,71), which are particularly abundant in the axon (51,72). Alterations in the expression of BORC and kinesin-1 subunits have been linked to psychiatric and neurological disorders (73)(74)(75)(76). In light of our findings, it would be of interest to investigate if aberrant transport of lysosomes in the axon contributes to the pathogenesis of these disorders.…”

Exome sequencing findings in 27 patients with myoclonic‐atonic epilepsy: Is there a major genetic factor?

“…SHROOM4 and FTSJ1 mutations have been reported in neurological impairments, including X‐linked ID . KLC2 mutations have been reported in neurodegenerative disorder combining spastic paraplegia, optic atrophy and neuropathy …”

Mechanisms and functions of lysosome positioning

“…Additional components of this machinery are mutated in several neurological diseases, including the p150-glued subunit of dynactin in ALS (Munch et al, 2004), Rab7 in Charcot-Marie-Tooth disease type 2B (Verhoeven et al, 2003), KIF1B in Charcot-Marie-Tooth disease type 2A (Zhao et al, 2001), KIF5A in hereditary spastic paraplegia type 10 (Reid et al, 2002) and KIF5C in cortical dysplasia with other brain malformations type 2 (Poirier et al, 2013). Similarly, upregulation of KLC2 is the cause of spastic paraplegia, optic atrophy and neuropathy (SPOAN) syndrome (Melo et al, 2015). Although altered lysosome dynamics could contribute to the pathogenesis of these diseases, the microtubule motors and regulators also mediate transport of additional organelles, such as synaptic vesicle precursors, mitochondria, retrograde transport carriers, and others.…”