Title

G418 Treatment Of Patients With A Nonsense Mutation In The X-Linked Cul4B Gene

Author(s)

Madison Williamson

School Name

Governor's School for Science and Math

Grade Level

12th Grade

Presentation Topic

Physiology and Health

Presentation Type

Mentored

Mentor

Mentor: Dr. Srivastava; Center for Molecular Studies, Greenwood Genetics Center

Oral Presentation Award

1st Place

Abstract

A nonsense mutation changes a sense codon into a premature stop codon that terminates the polypeptide chain prior to its completion. This creates a shortened protein that is ineffective. For patients with a nonsense mutation in the CUL4B gene, this creates moderate to severe intellectual disability as well as prominent phenotypes such as truncal obesity, short stature, and small feet. Previous studies found that nonsense mutations can be suppressed through the introduction of small molecular compounds, and more specifically, through the use of aminoglycosides, which bind to the proofreading centers of the ribosomal complex and allow for misincorporations of sense codons at the site. Aminoglycoside suppression therapy is a possible treatment option for nonsense mutations. However, it has not been widely tested against genetic disorders. This research explored the effects of aminoglycoside treatment for nonsense mutations in X-linked genes that resulted in intellectual disability. We tested the effects of G418 on the metabolic rates and ability to produce full-length protein in patient samples with nonsense mutations in the CUL4B gene, a commonly mutated gene resulting in intellectual disability. G418 was able to increase the amount of full-length CUL4B protein produced based on Western Blots, and increased the metabolism of patient cells. However, further studies are needed to reduce toxicity levels and improve the read through.

Location

Owens 107

Start Date

4-16-2016 12:00 PM

COinS
 
Apr 16th, 12:00 PM

G418 Treatment Of Patients With A Nonsense Mutation In The X-Linked Cul4B Gene

Owens 107

A nonsense mutation changes a sense codon into a premature stop codon that terminates the polypeptide chain prior to its completion. This creates a shortened protein that is ineffective. For patients with a nonsense mutation in the CUL4B gene, this creates moderate to severe intellectual disability as well as prominent phenotypes such as truncal obesity, short stature, and small feet. Previous studies found that nonsense mutations can be suppressed through the introduction of small molecular compounds, and more specifically, through the use of aminoglycosides, which bind to the proofreading centers of the ribosomal complex and allow for misincorporations of sense codons at the site. Aminoglycoside suppression therapy is a possible treatment option for nonsense mutations. However, it has not been widely tested against genetic disorders. This research explored the effects of aminoglycoside treatment for nonsense mutations in X-linked genes that resulted in intellectual disability. We tested the effects of G418 on the metabolic rates and ability to produce full-length protein in patient samples with nonsense mutations in the CUL4B gene, a commonly mutated gene resulting in intellectual disability. G418 was able to increase the amount of full-length CUL4B protein produced based on Western Blots, and increased the metabolism of patient cells. However, further studies are needed to reduce toxicity levels and improve the read through.