DNA variants within protein- coding genes have been primarily found to cause disease through one of four different effects on protein function (Fig. 1). The most common effect by far is a loss of function of the protein. Many important conditions arise, however, from other mechanisms: a gain of function, the acquisition of a novel property by the affected protein, or the expression of a gene at the wrong time (heterochronic expression) and/ or in the wrong place (ectopic expression).

Fig1. A general outline of the mechanisms by which disease- causing variants produce disease. Variants in the coding region result in structurally abnormal proteins that have a loss or gain of function or a novel property that causes disease. Variants in noncoding sequences are of two general types: those that alter the stability or splicing of the messenger RNA (mRNA) and those that disrupt regulatory elements or change gene dosage. Variants in regulatory elements alter the abundance of the mRNA or the time or cell type in which the gene is expressed. Variants in either the coding region or regulatory domains can decrease the amount of the protein produced. HPFH, Hereditary persistence of fetal hemoglobin.

Loss- of- Function Variants

The loss of function of a gene may result from alteration of its coding, regulatory, or other critical sequences due to nucleotide substitutions, deletions, insertions, or rearrangements. A loss of function due to deletion, leading to a reduction in gene dosage, is exemplified by the α- thalassemias, which are most commonly due to deletion of α- globin genes (see later discussion); by chromosome- loss diseases, such as monosomies like Turner syndrome; and by acquired somatic variants that occur in tumor- suppressor genes in many cancers, such as retinoblastoma. Many other types of variants can also lead to a complete loss of function, and all are illustrated by the β- thalassemias, a group of hemoglobinopathies that result from a reduction in the abundance of β- globin, one of the major adult hemoglobin proteins in red blood cells.

The severity of a disease due to loss- of- function variants generally correlates with the amount of function lost. In many instances, the retention of even a small percent of residual function by the abnormal protein greatly reduces the severity of the disease.

Gain- of- Function Variants

 Variants may also enhance one or more of the normal functions of a protein; in a biologic system, however, more is not necessarily better, and disease may result. It is critical to recognize when a disease is due to a gain- of- function variant because the treatment must necessarily differ from disorders due to other mechanisms, such as loss- of- function variants. Gain- of- function variants fall into two broad classes:

• Variants that increase the production of a normal protein. Some variants cause disease by increasing the synthesis of a normal protein in cells in which the protein is normally present. The most common variants of this type are due to increased gene dos age, which generally results from duplication of part or all of a chromosome. As discussed in Chapter 6, the classic example is trisomy 21 (Down syndrome), which is due to the presence of three copies of chromosome 21. Other important diseases arise from the increased dosage of single genes, including one form of familial Alzheimer disease due to a duplication of the amyloid precursor protein (βAPP) gene, and the peripheral nerve degeneration Charcot- Marie- Tooth disease type 1 A, which generally results from duplication of the gene for peripheral myelin protein 22 (PMP22).

• Variants that enhance one normal function of a protein. Rarely, a variant in the coding region may increase the ability of each protein molecule to perform one or more of its normal functions, even though this increase is detrimental to the overall physiologic role of the protein. For example, the missense variant that creates hemoglobin Kempsey locks hemoglobin into its high oxygen affinity state, thereby reducing oxygen delivery to tissues. Another example of this mechanism is the missense variation in the FGFR3 gene that causes achondroplasia, the most common skeletal dysplasia.

Novel Property Variants

In a few diseases, a change in the amino acid sequence confers a novel property on the protein, without necessarily altering its normal functions. The classic example of this mechanism is sickle cell disease, which, as we will see later in this chapter, is due to an amino acid substitution that has no effect on the ability of sickle hemoglobin to transport oxygen. Rather, unlike normal hemoglobin, sickle hemoglobin chains aggregate when they are deoxygenated and form abnormal polymeric fibers that deform red blood cells. That novel property variants are infrequent is not surprising because most amino acid substitutions are either neutral or detrimental to the function or stability of a protein that has been finely tuned by evolution.

Variants Associated With Heterochronic or Ectopic Gene Expression

 An important class of variants includes those that lead to inappropriate expression of the gene at an abnormal time or place. These variants occur in the regulatory regions of the gene. Cancer can be driven by expression of a gene that normally promotes cell proliferation— a proto-oncogene— in cells in which the gene is not normally expressed. Some variants in hemoglobin regulatory elements lead to the continued expression in adults of the γ- globin gene, which is normally expressed at high levels only in fetal life. Such γ- globin gene variants cause a benign phenotype called hereditary persistence of fetal hemoglobin (Hb F), as we explore later in this chapter.

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مواضيع ذات صلة

Human Hemoglobin and Associated Diseases

The Relationship Between Genotype and Phenotype in Genetic Disease

HNF1A and HNF4A (Transcription factor MODY)

Categories of Epigenetic disorders

Epigenetics in Development

Mosaicism

Pseudoautosomal inheritance

Characteristics of autosomal recessive inheritance

Patterns of Inheritance

Pedigrees

Genotype and Phenotype

Genetics in the Diagnosis of Celiac Disease: Role of HLA DQ2 and DQ8