Chapter 15, Problem 1CS

CASE STUDY |A mysterious muscular dystrophy

A man in his early 30s suddenly developed weakness in his hands and neck, followed a few weeks later by burning muscle pain–all symptoms of late-onset muscular dystrophy. His internist ordered genetic tests to determine whether he had one of the inherited muscular dystrophies, focusing on Becker muscular dystrophy, myotonic dystrophy Type I, and myotonic dystrophy Type II. These tests were designed to detect mutations in the related dystrophin, DMPK, and ZNF9 genes. The testing ruled out Becker muscular dystrophy. While awaiting the results of the DMPK and ZNF9 gene tests, the internist explained that the possible mutations were due to expanded tri- and tetranucleotide repeats, but not in the protein-coding portion of the genes. She went on to say that the resulting disorders were due not to changes in the encoded proteins, which appear to be normal, but instead to altered RNA splicing patterns, whereby the RNA splicing remnants containing the nucleotide repeats disrupt normal splicing of the transcripts of other genes. This discussion raises several interesting questions about the diagnosis and genetic basis of the disorders.

What is alternative splicing, where does it occur, and how could disrupting it affect the expression of the affected gene(s)?

Summary Introduction

Case summary:

A man experiences all the symptoms of late-onset muscular dystrophy including weakness in neck and hands and burning muscle pain. He has been prescribed several tests to detect mutations out of them Becker muscular dystrophy ruled out, results waited for DMPK and ZNF9 gene tests, so possible mutations were due to tri- and tetranucleotide repeats rather by changes to altered ribonucleotide acid (RNA) splicing patterns.

He has undergone different genetic tests to detect mutations in ZNF9, dystrophin, and DMPK.

Internist said that the disorder is due to changes in RNA splicing patterns and not in the protein-coding portions of the genes as the proteins appear to be normal.

Characters in the case:

A man with the symptoms of muscular dystrophy.

Adequate information:

Gene tests are the test to diagnose changes in chromosomal genes or proteins. These are mainly for abnormal chromosome number and mutations, which lead to inherited or rare disorder.

To determine:

Definition of alternative splicing and its occurrence, and the effects on expression of affected genes if it is disrupted.

Explanation of Solution

Given information:

A man with symptoms like muscular pain and weakness in hands and neck. Genetic test reveals Becker muscular dystrophy in this case, which is associated with the alteration in RNA splicing.

Alternate splicing also called as deferential splicing is the process occurs during gene expression resulting in different forms of mRNA from the identical pre-mRNA molecules, so we can say expression of a single gene leads to the formation of multiple proteins. In this process, the particular exons of a gene may be included or excluded from the final product of processed RNA. Resulting in changes in amino acids sequences and in there functioning. It occurs in spliceosome after the pre-mRNA has been transcribed.

Disruption in RNA processing can lead to miss-splicing of multiple transcripts, while alterations at single nucleotide lead to differences in single genes and thus in final product mRNA from a mutated gene. In case of muscular dystrophy, there is no change is recorded in protein products while the main cause is the accumulation of RNA in the nucleus, which have the toxic effects on the cells.

Conclusion

Hence, it can be concluded that Alternate splicing is a regulatory mechanism in eukaryotes, which removes or adds exons in the pre-mRNA polypeptide. However, alterations in these mechanisms lead to many inherited disorders because it will change the amino acid sequence and genes functioning.