In recent years, a new mechanism of posttranslational regulation of plasma LDL levels has been elucidated, wherein an enzyme referred to as PCSK9 causes intracellular degradation of LDL receptors in hepatocytes, before they reach the cell surface. With fewer LDL receptors on the cell surface, there is reduced uptake of plasma LDL, leading to hypercholesterolemia. Families with activating mutations of the gene PCSK9, which codes for the enzyme, have many features similar to classic familial hypercholesterolemia.
The discovery of the critical role of LDL receptors in cholesterol homeostasis has led to the rational design of the statin family of drugs that are now widely used to lower plasma cholesterol. They inhibit the activity of HMG-CoA reductase and thus promote greater synthesis of LDL receptors (
Fig. 7.2 ). However, the upregulation of LDL receptors is accompanied by a compensatory increase in PCSK9 levels, which dampens the effects of statins. Therefore, agents that antagonize PCSK9 enzymatic function have been developed, and large clinical trials have shown the benefits using such inhibitors in patients with refractory hypercholesterolemia.
FamilialhypercholesterolemiaisanautosomaldominantdisordercausedbymutationsinthegeneencodingtheLDLreceptor.ActivatingmutationsofPCSK9(farlesscommon),whichdegradesLDLreceptors,alsocauseasimilarphenotype.
PatientsdevelophypercholesterolemiaasaconsequenceofimpairedtransportofLDLintothecells.
Inheterozygotes,elevatedserumcholesterolgreatlyincreasestheriskofatherosclerosisandresultantcoronaryarterydisease;homozygoteshaveanevengreaterincreaseinserumcholesterolandahigherfrequencyofischemicheartdisease.Cholesterolalsodepositsalongtendonsheathstoproducexanthomas.
Cystic fibrosis (CF) is a disorder of epithelial ion transport affecting fluid secretion in exocrine glands and the epithelial linings of the respiratory, gastrointestinal, and reproductive tracts. The ion transport defects lead to http://ebooksmedicine.net
Mendelian Disorders: Diseases Caused by Single-Gene Defects251 abnormally viscid mucous secretions that block the airways and the pancreatic ducts which in turn are responsible for the two most important clinical manifestations: recurrent and chronic pulmonary infections and pancreatic insufficiency. In addition, although the exocrine sweat glands are structurally normal (and remain so throughout the course of this disease), a high level of sodium chloride in the sweat is a consistent and characteristic biochemical abnormality in CF. At the same time, it must be remembered that CF can present with a bewilderingly variable set of clinical findings. This variation in phenotype results from diverse mutations in the CF-associated gene, tissue-specific effects of loss of the CF gene’s function, and the influence of disease modifier genes.
With an incidence of 1 in 2500 live births in the United States, CF is the most common lethal genetic disease that affects white populations. The carrier frequency in the United States is 1 in 20 among Caucasians but significantly lower among African Americans, Asians, and Hispanics. CF follows simple autosomal recessive transmission, although even heterozygous carriers have a predisposition toward pulmonary and pancreatic disease at higher rates than the general population.
The primary defect in CF is reduced production, or abnormal function of an epithelial chloride channel protein encoded by the CF transmembrane conductance regulator (CFTR) gene. Disruptive mutations in CFTR render the epithelial membranes relatively impermeable to chloride ions (