Proteins carry out an astounding number of functions, some of which are presented in Fig. 1. Pathogenic variants in virtually every functional class of protein can lead to genetic disorders. In this chapter we describe important genetic diseases that affect representative proteins selected from the groups shown in Fig. 1; other proteins listed, as well as the conditions associated with them, are described in the Cases section.

Fig1. Examples of the classes of proteins associated with diseases with a strong genetic component (most are monogenic), and the part of the cell in which those proteins normally function. CDG1b (MPI-CDG), Congenital disorder of glycosylaton type 1b (mannosephosphate isomerase, congenital disorder of glycosylation); CFTR, cystic fibrosis transmembrane regulator; FMRP, fragile X messenger ribonucleoprotein; HLA, human leukocyte antigen; LDL, low-density lipoprotein; MELAS, mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes; PKU, phenylketonuria.

Housekeeping Proteins and Specialty Proteins in Genetic Disease

Proteins can be separated into two general classes on the basis of their pattern of expression. Housekeeping proteins are present in virtually every cell and have fundamental roles in the maintenance of cell structure and function; tissue-specific specialty proteins are produced in one or few cell types and have unique functions that contribute to the individuality of the cells in which they are expressed. Most cell types in humans express 10,000 to 15,000 protein-coding genes. Knowledge of the tissues in which a protein is expressed, particularly at high levels, may help in understanding the pathogenesis of a disease.

Two broad generalizations can be made about the relationship between the site of a protein’s expression and the site of disease.

• First (and somewhat intuitively), pathogenic variants in a tissue-specific protein most often produce a dis ease restricted to that tissue. However, there may be secondary effects on other tissues. Pathogenic variants in tissue-specific proteins may cause abnormalities primarily in organs that do not express the protein at all; ironically, the tissue expressing the abnormal protein may be unaffected by the pathologic process. This situation is exemplified by PKU, discussed in depth in the next section. PKU is due to the absence of phenylalanine hydroxylase (PAH) activity in the liver, but it is the brain (which expresses very little of this enzyme), not the liver, that is damaged by the high blood levels of phenylalanine resulting from the lack of hepatic PAH.

• Second, although housekeeping proteins are expressed in most or all tissues, the clinical effects of pathogenic variants in such proteins are frequently limited to one or few tissues, for at least two reasons. Most often, the housekeeping protein in question is normally expressed abundantly in one or few tissues where it serves a specialty function. This situation is illustrated by Tay-Sachs disease. The enzyme affected in this disorder is hexosaminidase A, which is expressed in virtually all cells, but its absence leads to a fatal neurodegeneration while leaving nonneuronal cell types unscathed. In other instances, another protein with overlapping biologic activity may be expressed in the unaffected tissue, thereby lessening the impact of the loss of function by the variant allele – a situation known as genetic redundancy. Unexpectedly, even pathogenic variants in genes seeming as essential to every cell, such as actin, can result in viable offspring.

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مواضيع ذات صلة

Lysosomal Storage Diseases: A Unique Class of Enzymopathies

Aminoacidopathies

Renal cysts and diabetes (HNF1B MODY)

Maternally inherited diabetes and deafness

Genetic testing in neonatal diabetes

Human Hemoglobin and Associated Diseases

The Relationship Between Genotype and Phenotype in Genetic Disease

Effect of Pathogenic Variants on Protein Function

HNF1A and HNF4A (Transcription factor MODY)

Categories of Epigenetic disorders

Epigenetics in Development

Mosaicism