Ebook Genetics in medicine (8/E): Part 2

Part 2 book "Genetics in medicine" includes content: The molecular basis of genetic disease; the molecular, biochemical, and cellular basis of genetic disease; the treatment of genetic disease; developmental genetics and birth defects; cancer genetics and genomics; risk assessment and genetic counseling; prenatal diagnosis and screening; application of genomics to medicine and personalized health care; ethical and social issues in genetics and genomics.
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Ebook Genetics in medicine (8/E): Part 2 C H A P T E R 11  The Molecular Basis of Genetic Disease General Principles and Lessons from the Hemoglobinopathies The term molecular disease, introduced over six decades all inherited disorders, but even here, knowledge is ago, refers to disorders in which the primary disease- incomplete—despite its being the first molecular disease causing event is an alteration, either inherited or to be recognized, more than 65 years ago. acquired, affecting a gene(s), its structure, and/or its expression. In this chapter, we first outline the basic THE EFFECT OF MUTATION ON genetic and biochemical mechanisms underlying mono- genic or single-gene disorders. We then illustrate them PROTEIN FUNCTION in the context of their molecular and clinical conse- Mutations involving protein-coding genes have been quences using inherited diseases of hemoglobin—the found to cause disease through one of four different hemoglobinopathies—as examples. This overview of effects on protein function (Fig. 11-1). The most com- mechanisms is expanded in Chapter 12 to include other mon effect by far is a loss of function of the mutant genetic diseases that illustrate additional principles of protein. Many important conditions arise, however, genetics in medicine. from other mechanisms: a gain of function, the acqui­ A genetic disease occurs when an alteration in the sition of a novel property by the mutant protein, or DNA of an essential gene changes the amount or func- the expression of a gene at the wrong time (hetero­ tion, or both, of the gene products—typically messenger chronic expression) and/or in the wrong place (ectopic RNA (mRNA) and protein but occasionally specific expression). noncoding RNAs (ncRNAs) with structural or regula- tory functions. Although almost all known single-gene disorders result from mutations that affect the function Loss-of-Function Mutations of a protein, a few exceptions to this generalization are The loss of function of a gene may result from alteration now known. These exceptions are diseases due to muta- of its coding, regulatory, or other critical sequences due tions in ncRNA genes, including microRNA (miRNA) to nucleotide substitutions, deletions, insertions, or genes that regulate specific target genes, and mitochon- rearrangements. A loss of function due to deletion, drial genes that encode transfer RNAs (tRNAs; see leading to a reduction in gene dosage, is exemplified by Chapter 12). It is essential to understand genetic disease the α-thalassemias       (Case 44), which are most com- at the molecular and biochemical levels, because this monly due to deletion of α-globin genes (see later dis- knowledge is the foundation of rational therapy. In this cussion); by chromosome-loss diseases       (Case 27), such chapter, we restrict our attention to diseases caused by as monosomies like Turner syndrome (see Chapter defects in protein-coding genes; the study of phenotype 6)       (Case 47); and by acquired somatic mutations—often at the level of proteins, biochemistry, and metabolism deletions—that occur in tumor-suppressor genes in constitutes the discipline of biochemical genetics. many cancers, such as retinoblastoma       (Case 39)       (see By 2014, the online version of Mendelian Inheritance Chapter 15). Many other types of mutations can also in Man listed over 5500 phenotypes for which the lead to a complete loss of function, and all are illus- molecular basis is known, largely phenotypes with auto- trated by the β-thalassemias       (Case 44)       (see later discus- somal and X-linked inheritance. Although it is impres- sion), a group of hemoglobinopathies that result from sive that the basic molecular defect has been found in a reduction in the abundance of β-globin, one of the so many disorders, it is sobering to realize that the major adult hemoglobin proteins in red blood cells. pathophysiology is not entirely understood for any The severity of a disease due to loss-of-function genetic disease. Sickle cell disease       (Case 42), discussed mutations generally correlates with the amount of func- later in this chapter, is among the best characterized of tion lost. In many instances, the retention of even a 195 196 THOMPSON & THOMPSON GENETICS IN MEDICINE MUTATION Mutations affecting Mutations in Mutations disrupting gene regulation coding region RNA stability or dosage or RNA splicing Protein abnormal Protein structure normal • Hb Hammersmith ...