In most cases, rare genetic diseases are produced by a single mutation in a single gene, to produce a rare disease that typically develops early in life, often with a rather uniform clinical presentation. In Chapter 7, some of the complexities of single-gene disorders are discussed. Here is an excerpt:
A single gene may produce a protein product whose function varies depending on the specific site and type of mutation in the gene. Hence, variations in a gene can produce different diseases. For example, different mutations of the same gene, desmoplakin, cause the following diseases:
- Arrhythmogenic right ventricular dysplasia-8
- Dilated cardiomyopathy with woolly hair and keratoderma
- Lethal acantholytic epidermolysis bullosa
- Keratosis palmoplantaris striata II
- Skin fragility-woolly hair syndrome
In some cases, variation in the sites of mutations in a gene does not produce different diseases, but may account for one disease with different levels of severity. For example, in the case of Wiskott–Aldrich syndrome, discussed in Section 7.1, mutations that truncate the protein product of the WAS gene will produce severe disease, while mutations that produce changes in single amino acids, without changing the length of the protein, will tend to produce mild disease [14].
In other cases, the [epigenetic] gain or loss of methylation at a gene site may produce disorders of nearly opposite clinical features. For example, the H19 differentially methylated region is a site on chromosome 11p15.5 in which microdeletions occur in some cases of Beckwith–Wiedemann syndrome and Russell–Silver syndrome. Opposite methylation patterns in the H19 differentially methylated region will cause Beckwith–Wiedemann syndrome when there is gain-of-methylation and Russell–Silver syndrome when there is loss-of-methylation (see Glossary item, Gain-of-function) [15]. Beckwith–Wiedemann syndrome is characterized by tissue overgrowth and tumor formation [16]. Russell–Silver syndrome is characterized by dwarfism. The role of methylation in epigenetic regulation will be described in further detail in Chapter 10.
If single-gene disorders can be complex, try to imagine the biological complexity of common diseases, which typically have a polygenic origin (i.e., multiple genes involved), with multiple environmental influences, with symptoms developing in steps, sometimes extending over decades! The difficulty understanding the biology of the common diseases, in contrast with the relative ease of understanding the rare diseases, is a topic that is explored in depth in the book.
I urge you to read more about this book. There's a good preview of the book at the Google Books site.
- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, disease complexity, complex diseases, genetics of disease, monogenic disease, polygenic disease, orphan disease, orphan drugs, Beckwith-Wiedemann, Wiskott-Aldrich
