Heritable defects

Genotoxicity studies are required to identify compounds that can induce genetic damage ranging from single point gene mutations to gross alterations of chromosomal structure. Such effects are taken as indicative of the potential to cause cancer or heritable defects in humans. A standard battery of three types of test is recommended ... 

The effects of radiation on a person depend not only on the dosage but also on the length of time in which the dose was received. A series of small doses has less overall effect than these dosages given all at once. A single dose of about 500 rems is fatal to most people, and survival from a much smaller dose can be uncertain or leave the person chronically ill. Detectable effects are seen with doses as low as 30 rems. Continuous exposure to such low levels of radiation may result in cancer or leukemia. At even lower levels, the answer to whether the radiation dose is safe depends on the possible genetic effects of the radiation. Because radiation can cause chromosome damage, heritable defects are possible. 

May cause heritable genetic damage May cause birth defects... 

Felix R Channelopathies ion channel defects linked to heritable clinical disorders. J Med Genet 2000 37 729. 

Finally, we consider physiological expression or suppression, and the long latent period between carcinogen treatment and tumor appearance. While it makes sense to think in terms of phenotypic lag, clonal growth, vascularization, immuno-suppression, and other phenomena, we just do not know enough today to define clear-cut experimental approaches. However, at the human level, the undesirable endpoints of this series of processes are clear teratologic syndromes, cancer, and heritable birth defects. 

Aberrations in chromosomes or chromatids, which are sometimes microscopically visible, may arise during mitotic division when newly divided chromosomes fail to separate or do so incorrectly. The absence of a chromosome is usually lethal, and an excess is often poorly tolerated, giving rise to serious defects. Aberrations of the sex chromosomes are more readily tolerated, however. Chromosome aberrations may be caused by foreign compounds as indicated in the section on mutagenesis (see chap. 6). However, those cells with aberrations seem to be rapidly eliminated and so may contribute to cell death rather than a heritable mutation. 

Fibrillin microfibrils are widely distributed extracellular matrix assemblies that endow elastic and non elastic connective tissues with long-range elasticity. They direct tropoelastin deposition during elastic fibrillogenesis and form an outer mantle for mature elastic fibers. Microfibril arrays are also abundant in dynamic tissues that do not express elastin, such as the ciliary zonules of the eye. Mutations in fibrillin-1—the principal structural component of microfibrils—cause Marfan syndrome, a heritable disease with severe aortic, ocular, and skeletal defects. Isolated fibrillin-rich microfibrils have a complex 56 nm beads-on-a-string appearance the molecular basis of their assembly and... 

Detailed comparisons of induced skeletal and eye anomalies in the mouse with human skeletal and eye defects are desirable. Systems for measuring heritable translocations in postspermatogonial cells in the mouse have been developed and can be extended to estimate the risk to corresponding human stages.1314... 

Four classes of LDL receptor mutations have been identified. Class 1 mutations are characterized by the failure of expression of the receptor protein. It is possible, however, that a modified protein is produced but it is not recognized as an LDL receptor protein. Class 2 mutations involve a nonsense mutation (premature termination of protein synthesis Chap. 17), and result in a defect in the transfer of the receptor from the endoplasmic reticulum to the cell membranes. This class of mutation is common in Afrikaners and Lebanese. The Watanabe heritable hyperlipidemic rabbit (WHHL) is an animal model which has a Class 2 defect and has been used extensively for the study of familial hypercholesterolemia. Class 3 mutations result in abnormal binding of LDL. This can be caused by alterations in the amino acid sequence of Domain 1. Class 4 mutations are those with defective internalization due to the receptor s inability to be located in coated pits. This is the result of mutations in the fifth, C-terminal domain. 

The conversion of procollagen to collagen by removal of propeptides seems to be essential for the formation of collagen fibrils. This supposition is supported by studies of two heritable diseases, one found in humans and the other in cattle, sheep, and cats. In both, the defect lies in the removal of N-terminal propeptides and results in impaired fibril formation. The human disorder is the type VII variant of Ehlers-Danlos syndrome (Table 25-5). Affected individuals exhibit marked joint hypermobility, dislocation of joints, short stature, and minor changes in skin elasticity. Their skin fibroblasts show normal... 

Osteopetrosis, also known as marble bone disease, describes a group of heritable disorders that are centered on a defect in osteoclast-mediated bone resorption. There are four autosomal recessive and one autosomal dominant forms of osteopetrosis (Table 35.4) (16). It generally is characterized by abnormally dense, brittle bone and increased skeletal mass. Unlike osteoporosis, this disorder results from decreased osteoclast activity, which has an effect on both the shape and structure of the bone. In very extreme cases, the medullary cavity, which houses bone marrow, fills with new bone, and production of hematopoietic cells is hampered. Like osteoporosis, this disease can be detected radiographically and appears as though there is a bone within a bone. There is limited evidence that bisphosphonates can induce osteopetrosis via their inhibition of osteoclast activity (17). 

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