A 45-year-old man comes to the physician because of involuntary movements and behavioral disturbance. He has frequent, jerky, irregular movements of his upper extremities that have progressively worsened over the past month. His family and friends also say that he has become increasingly irritable over the past year. Genetic testing shows a mutation affecting the huntingtin protein that causes transcriptional repression of a number of other genes. Which of the following mechanisms is most likely responsible for the decreased gene expression seen in this patient?

Question

A 45-year-old man comes to the physician because of involuntary movements and behavioral disturbance.  He has frequent, jerky, irregular movements of his upper extremities that have progressively worsened over the past month.  His family and friends also say that he has become increasingly irritable over the past year.  Genetic testing shows a mutation affecting the huntingtin protein that causes transcriptional repression of a number of other genes.  Which of the following mechanisms is most likely responsible for the decreased gene expression seen in this patient?

Quizplus · Accepted Answer

11ec160b_3784_e3e3_9249_6bfb544a6b0d_MD0001_00 Huntington disease is an autosomal-dominant neurodegenerative disease caused by an increase in the number of CAG trinucleotide repeats in the gene that codes for the huntingtin protein. Expansion of the protein's polyglutamine region results in a gain-of-function that leads to pathological interaction with other proteins, including various transcription factors. Transcriptional repression (silencing) is one of the mechanisms by which mutated huntingtin is thought to cause disease. Regulation of transcription occurs in part due to the presence of histones, small proteins that complex with DNA to help compact the strands. Histones can undergo a variety of modifications (eg, methylation, acetylation, phosphorylation) that affect the accessibility of the genome for transcription. Acetylation of histones weakens the DNA-histone bond and makes DNA segments more accessible for transcription factors and RNA polymerases, enhancing gene transcription. In Huntington disease, abnormal huntingtin causes increased histone deacetylation, silencing the genes necessary for neuronal survival. As a result, one of the treatment options under investigation includes histone deacetylase inhibitors that help upregulate survival genes. (Choice A) DNA methylation is an epigenetic modification that acts to inhibit gene transcription. Hypermethylation of the promotor region of a gene results in transcriptional silencing; hypomethylation improves gene expression. (Choice C) The manifestations of Huntington disease are caused by a deleterious gain of function mutation. Although the normal function of huntingtin is not completely understood, it is known to play a critical role in embryonic development; loss of huntingtin results in embryonic death. (Choice D) Homeodomain (homeobox) genes are critical for the sequential development of organs and tissues along the body axis during embryogenesis. Mutations affecting these genes cause alterations in body structure, leading to congenital malformations or spontaneous abortion. (Choice E) Thymidine dimerization is a mechanism of DNA damage induced by ultraviolet radiation. Educational objective: Hypo-acetylated histones bind tightly to DNA and prevent transcription of genes in their associated regions. Alteration of gene expression in Huntington disease occurs in part due to deacetylation of histones. This prevents the transcription of certain genes that code for neurotrophic factors, contributing to neuronal cell death. __________ References: Mechanisms of disease: histone modifications in Huntington's disease. (http://www.ncbi.nlm.nih.gov/pubmed/16932577) Epigenetic mechanisms of neurodegeneration in Huntington's disease. (http://www.ncbi.nlm.nih.gov/pubmed/24006238)

A 45-Year-Old Man Comes to the Physician Because of Involuntary