monogenic diseases
All mendelian diseases are the result of expressed mutations in single genes of large effect. Most of these are recessive and therefore do not have serious phenotypic effects. About 80% to 85% of these mutations are familial. The remainder represent new mutations acquired de novo by an affected individual
The identification of genes associated with hereditary disorders has contributed to improving medical care and to a better understanding of gene functions, interactions, and pathways.
More than 1,800 known monogenic hereditary disorders have been described. However, there are well over 1500 Mendelian disorders whose molecular basis remains unknown.
Some autosomal mutations produce partial expression in the heterozygote and full expression in the homozygote.
Although gene expression is usually described as dominant or recessive, in some cases, both of the alleles of a gene pair may be fully expressed in the heterozygote, a condition called codominance. Histocompatibility and blood group antigens are good examples of codominant inheritance.
A single mutant gene may lead to many end effects, termed pleiotropism. Sickle cell anemia may serve as an example of pleiotropism. Conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity).
Types
autosomal dominant diseases
autosomal recessive diseases
X-linked diseases
Consequences
enzyme deficiency (enzyme defects)
- accumulation of the substrate (storage diseases)
- metabolic block with decreased amount of end product
- failure to inactivate a tissue-damaging substrate
defects in receptor proteins
defects in transport systems
genetically determined adverse reactions to drugs
alterations in structure, function, or quantity of nonenzyme proteins
- defects in structural proteins
- defects in cell growth regulating proteins
Pathogeny
Mutations involving single genes typically follow one of three patterns of inheritance: autosomal dominant, autosomal recessive, and X-linked. The general rules that govern the transmission of single-gene disorders are well known and are not repeated here.
Mendelian disorders result from alterations involving single genes. The genetic defect may lead to the formation of an abnormal protein or a reduction in the output of the gene product. Gene mutations may affect protein synthesis by affecting transcription, mRNA processing, or translation.
The phenotypic effects of a mutation may result directly, from abnormalities in the protein encoded by the mutant gene, or indirectly, owing to interactions of the mutant protein with other normal proteins. For example, all forms of Ehlers-Danlos syndrome (EDS) are associated with abnormalities of collagen. In some forms (e.g., vascular type), there is a mutation in one of the collagen genes, whereas in others (e.g., kyphoscoliosis type), the collagen genes are normal, but there is a mutation in the gene that encodes lysyl hydroxylase, an enzyme essential for the cross-linking of collagen. In these patients, collagen weakness is secondary to a deficiency of lysyl hydroxylase.
Virtually any type of protein may be affected in single-gene disorders and by a variety of mechanisms. To some extent, the pattern of inheritance of the disease is related to the kind of protein affected by the mutation.
The mechanisms involved in single-gene disorders can be classified into four categories:
(1) enzyme defects and their consequences;
(2) defects in membrane receptors and transport systems;
(3) alterations in the structure, function, or quantity of nonenzyme proteins;
(4) mutations resulting in unusual reactions to drugs
See also
References
Brinkman RR, Dube MP, Rouleau GA, Orr AC, Samuels ME. Human monogenic disorders - a source of novel drug targets. Nat Rev Genet. 2006 Apr;7(4):249-60. PMID: 16534513
O’Connor TP, Crystal RG. Genetic medicines: treatment strategies for hereditary disorders. Nat Rev Genet. 2006 Apr;7(4):261-76. PMID: 16543931
Antonarakis SE, Beckmann JS. Mendelian disorders deserve more attention. Nat Rev Genet. 2006 Apr;7(4):277-82. PMID: 16534515