Disease phenotype

Knocking out genes and identification of mutations in the human genes provide information on the role of AQPs in normal physiology. The lack of some AQPs directly results in a disease phenotype, while the physiological role of many becomes clear when the putative function is challenged. 

Single-base substitutions, which affect the amino acid sequence of proteins and lead to altered protein function, are the most frequent type of polymorphisms associated with many disease phenotypes as well as with variation in drag response... 

Brouillet, E., Conde, F., Beal, M. F. and Hantraye, P. Replicating Huntington s disease phenotype in experimental animals. Prog. Neurobiol. 59 427-468,1999. 

If only one copy of an allele is required for its phenotypic expression, the allele is dominant (i.e., it is observable in the heterozygous state). If two copies of the allele are required for its expression (i.e., the disease phenotype is observable only in the homozygous state), it is recessive. The expression of the recessive alleie is thus hidden in the heterozygote. The terms dominant and recessive provide a convenient classification of genetic diseases, as seen below. If two different alleles are both phenotypicaUy expressed in a heterozygous genotype, the alleles are said to be codominant. 

As in autosomal dominant inheritance, the disease phenotype is seen in multiple generations of a pedigree skipped generations are relatively unusual. 

Locus heterogeneity exists when the same disease phenotype can be caused by mutations in different loci. Locus heterogeneity becomes especially important when genetic testing is performed by testing for mutations at specific loci. 

In studying a large number of families with a small deletion in a specific chromosome region, it is noted that the disease phenotype is distinctly different when the deletion is inherited from the mother as opposed to the father. What is the most likely explanation ... 

Answer B. In-frame deletions or insertions typically produce an altered protein product (dystrophin), but the alteration is mild enough so that Becker muscular dystrophy results. Frame-shifts usually produce a truncated protein because a stop codon is eventually encountered. The truncated protein is degraded, resulting in an absence of dystrophin and a more severe disease phenotype. 

Under mitochondrial inheritance (choice B), only an affected mother can transmit the disease phenotype the offspring of affected males are always unaffected. 

As shown in Fig. 1.1, the integration of pharmacogenomics and systems biology can help elucidate the mechanisms of diseases and drug actions at various levels and connect information between different levels. For example, altered genetic structure may cause malfunctions at the molecular level, which would influence the downstream interactions, pathways, and networks at the cellular level. Such changes may then lead to tissue or organ disorders that are disease phenotypes reflected as... 

Gene Variant/aUele Disease/ phenotype Pharmacology Reference... 

The GRK family consists of seven well-characterized enzymes. These enzymes are distinguished by (1) the structural homology within the family (2) the specific amino acid sequences that a given GRK can phosphorylate (3) enzyme kinetics (169,181) and (4) GPCR disease phenotypes that are often manifested by dysregula-tion of GRK activity. Gain-of-function GPCR mutations are frequently found to be constitutively phosphorylated. Conversely, inadequate receptor desensitization and sequestration often result. 

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