The Immense Dystrophin Gene

The most common and devastating of the muscular dystrophies is Duchenne muscular dystrophy, a fatal disease that strikes nearly 1 in 3500 males. At birth, affected boys appear normal. The first symptom is mild muscle weakness appearing between 3 and 5 years of age: the child stumbles frequently, has difficulty climbing stairs, and is unable to rise from a sitting position. In time, the arm and leg muscles become progressively weaker. By age 11, those affected are usually confined to a wheel chair and, by age 20, most persons with Duchenne muscular dystrophy have died. At present, there is no cure for the disease.

Duchenne muscular dystrophy was first recognized in 1852, and the disease was fully described in 1861 by Benjamin A. Duchenne, a Paris physician. Even before Mendel's laws were discovered, physicians noticed its X-linked pattern of inheritance, remarking that the disease developed almost exclusively in males and seemed to be inherited through unaffected mothers. In spite of this early recognition of its hereditary basis, the biochemical cause of Duchenne muscular dystrophy remained a mystery until 1987.

In 1985, Louis Kunkel and his colleagues at Harvard Medical School observed a boy with Duchenne muscular dystrophy whose X chromosome had a visible deletion on the short arm. Reasoning that this boy's disease was caused by the absence of a gene within the deletion, they recognized that the deletion pointed to the location on the X chromosome of the gene responsible for Duchenne muscular dystrophy. Kunkel and his colleagues located and cloned the piece of DNA responsible for the disease. Shortly thereafter, the sequence of the gene was determined, and the protein that it encodes was isolated. This large protein, called dystrophin, consists of nearly 4000 amino acids and is an integral component of muscle cells. Persons with Duchenne muscular dystrophy lack functional dystrophin.

The dystrophin gene is among the most remarkable of all genes yet examined. It's huge, encompassing more than 2 million nucleotides of DNA. However, only about 12,000 of its nucleotides encode its amino acids. Why is the dystrophin gene so large? What are all those other nucleotides doing?

The unusual properties of the dystrophin gene make sense only in the context of RNA processing—the alteration of RNA after it has been transcribed. Dystrophin mRNA, like many eukaryotic RNAs, undergoes extensive processing after transcription, including the removal of large sections that are not required for translation. Chapter 13 focused on transcription—the process of RNA synthesis. In this chapter, we will examine the function and processing of RNA.

We begin by taking a careful look at the nature of the gene. Next, we examine messenger RNA, its structure, and how it is modified in eukaryotes after transcription. We'll also see how, through alternative pathways of RNA modification, one gene can produce several different proteins. Then, we turn to transfer RNA, the adapter molecule that forms the interface between amino acids and mRNA in protein synthesis. Finally, we examine ribosomal RNA, the structure and organization of rRNA genes, and how rRNAs are processed.

As we explore the world of RNA and its role in gene function, we will see evidence of two important characteristics of this nucleic acid. First, RNA is extremely versatile, both structurally and biochemically. It can assume a number of different secondary structures, which provide the basis for its functional diversity. Second, RNA processing and function frequently include interactions between two or more RNA molecules.

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