Duchenne muscular dystrophy (DMD)
Defective cytoskeletal protein dystrophin leads to impaired muscle function.
Defective blood clotting factor VIII leads to uncontrolled bleeding.
typic clues might be relevant to make guesses about the molecular basis of inherited diseases. An early example of successful guesswork was the hypothesis that sickle-cell anemia, known to be a disease of blood cells, might be caused by a defective hemoglobin. This idea led to identification of a specific amino acid substitution in hemoglobin that causes polymerization of the defective hemoglobin molecules, causing the sickle-like deformation of red blood cells in individuals who have inherited two copies of the Hbs allele for sickle-cell hemoglobin.
Most often, however, the genes responsible for inherited diseases must be found without any prior knowledge or reasonable hypotheses about the nature of the affected gene or its encoded protein. In this section, we will see how human geneticists can find the gene responsible for an inherited disease by following the segregation of the disease in families. The segregation of the disease can be correlated with the segregation of many other genetic markers, eventually leading to identification of the chromosomal position of the affected gene. This information, along with knowledge of the sequence of the human genome, can ultimately allow the affected gene and the disease-causing mutations to be pinpointed. I
Many Inherited Diseases Show One of Three Major Patterns of Inheritance
Human genetic diseases that result from mutation in one specific gene exhibit several inheritance patterns depending on the nature and chromosomal location of the alleles that cause them. One characteristic pattern is that exhibited by a dominant allele in an autosome (that is, one of the 22 human chromosomes that is not a sex chromosome). Because an autosomal dominant allele is expressed in the heterozygote, usually at least one of the parents of an affected individual will also have the disease. It is often the case that the diseases caused by dominant alleles appear later in life after the reproductive age. If this were not the case, natural selection would have eliminated the allele during human evolution. An example of an autosomal dominant disease is Huntington's disease, a neural degenerative disease that generally strikes in mid- to late life. If either parent carries a mutant HD allele, each of his or her children (regardless of sex) has a 50 percent chance of inheriting the mutant allele and being affected (Figure 9-44a).
A recessive allele in an autosome exhibits a quite different segregation pattern. For an autosomal recessive allele, both parents must be heterozygous carriers of the allele in order for their children to be at risk of being affected with the disease. Each child of heterozygous parents has a 25 percent chance of receiving both recessive alleles and thus being affected, a 50 percent chance of receiving one normal and one mutant allele and thus being a carrier, and a 25 percent chance of receiving two normal alleles. A clear example of an autosomal recessive disease is cystic fibrosis, which results from a defective chloride channel gene known as CFTR (Fig-
(a) Huntington's disease cT AHD/A+
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