A Multilayered Control of the Human Survival Motor Neuron Gene Expression by Alu Elements

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2017-11-01
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Seo, Joonbae
Singh, Natalia
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Ottesen, Eric
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Singh, Ravindra
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Biomedical Sciences

The Department of Biomedical Sciences aims to provide knowledge of anatomy and physiology in order to understand the mechanisms and treatment of animal diseases. Additionally, it seeks to teach the understanding of drug-action for rational drug-therapy, as well as toxicology, pharmacodynamics, and clinical drug administration.

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The Department of Biomedical Sciences was formed in 1999 as a merger of the Department of Veterinary Anatomy and the Department of Veterinary Physiology and Pharmacology.

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1999–present

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  • College of Veterinary Medicine (parent college)
  • Department of Veterinary Anatomy (predecessor, 1997)
  • Department of Veterinary Physiology and Pharmacology (predecessor, 1997)

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Abstract

Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Mutations or deletions of SMN1, which codes for SMN, cause spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Aberrant expression or localization of SMN has been also implicated in other pathological conditions, including male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. SMN2 fails to compensate for the loss of SMN1 due to skipping of exon 7, leading to the production of SMNΔ7, an unstable protein. In addition, SMNΔ7 is less functional due to the lack of a critical C-terminus of the full-length SMN, a multifunctional protein. Alu elements are specific to primates and are generally found within protein coding genes. About 41% of the human SMN gene including promoter region is occupied by more than 60 Alu-like sequences. Here we discuss how such an abundance of Alu-like sequences may contribute toward SMA pathogenesis. We describe the likely impact of Alu elements on expression of SMN. We have recently identified a novel exon 6B, created by exonization of an Alu-element located within SMN intron 6. Irrespective of the exon 7 inclusion or skipping, transcripts harboring exon 6B code for the same SMN6B protein that has altered C-terminus compared to the full-length SMN. We have demonstrated that SMN6B is more stable than SMNΔ7 and likely functions similarly to the full-length SMN. We discuss the possible mechanism(s) of regulation of SMN exon 6B splicing and potential consequences of the generation of exon 6B-containing transcripts.

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This article is published as Ottesen, Eric W., Joonbae Seo, Natalia N. Singh, and Ravindra N. Singh. "A multilayered control of the human Survival Motor Neuron gene expression by Alu elements." Frontiers in Microbiology 8 (2017): 2252. doi: 10.3389/fmicb.2017.02252. Posted with permission.

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Sun Jan 01 00:00:00 UTC 2017
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