Lesch Nyhan Syndrome and the Relation Between Genotype and Phenotype

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In 1962, Dr. William Nyhan and his student Michael Lesch examined a seriously ill boy with a strange combination of symptoms. The boy had blood in his urine, high concentrations of uric acid in his blood, and uncontrollable spasms in his arms and legs. He was mentally retarded and self-destructively bit his fingers and lips. After carefully studying the boy, Nyhan and Lesch came to the conclusion that he was afflicted by an undescribed disease. Soon other patients with similar symptoms were reported, and the disease became known as the Lesch-Nyhan syndrome.

One of the earliest symptoms of Lesche-Nyhan syndrome is the appearance of orange "sand" — actually uric acid crystals—in diapers a few weeks after birth. Within a year, the child begins to exhibit writhing movements of the hands and feet and involuntary spasms. About half of the children have seizures. After 2 or 3 years, some of the children exhibit compulsive self-mutilation—biting fingers, lips, the tongue, and the insides of the mouth.

Lesch-Nyhan syndrome develops almost exclusively in boys, and the trait is inherited as an X-linked recessive disorder; the presence of a defective gene on a male's single X chromosome causes the disease. In 1967, a team of scientists at the National Institutes of Health determined that the disease results from a defective copy of the gene that normally encodes the enzyme hypoxanthine-guanine phos-

phoribosyl transferase (HGPRT). As DNA and RNA are degraded in the cell, purines are liberated, and HGPRT salvages these purines and uses them to synthesize new RNA and DNA nucleotides. In people who have Lesch-Nyhan syndrome, a mutation in the gene for HGPRT changes the amino acid sequence of the enzyme, rendering it nonfunctional. The result is that purines are not recycled; they accumulate and are converted into uric acid. High levels of uric acid produce the symptoms of the disease.

Lesch-Nyhan syndrome illustrates the link between genotype and phenotype: a mutation in a gene affects a protein, which then produces the symptoms of the disease. Preceding chapters described how DNA encodes genetic information and how that information is transferred from DNA to RNA. In this chapter, we examine translation, the process by which the nucleotide sequence in mRNA specifies the amino acid sequence of a protein.

We begin by examining the molecular relation between genotype and phenotype. As with Lesch-Nyhan syndrome, the final phenotype may be complex, including biochemical, physiological, and behavioral traits, but it is ultimately caused by the protein that the gene encodes. We next study the genetic code—the instructions that specify the amino acid sequence of a protein—and then examine the mechanism of protein synthesis. Our primary focus will be on protein synthesis in bacterial cells, but we will highlight some of the differences in eukaryotic cells.

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