Medical brain notes 30

  NUCLEUS AND NUCLEOCYTOPLASMIC TRANSPORT The nucleus contains the genome of the cell stored as sequences of nucle-otide bases in DNA molecules most of which are contained in chromosomes  Other than a few mitochondrial genes, all the human genes are found here. Surprisingly, it seems that less than 5% of the three billion pairs of nucleotides constitute the less than 30 000 genes of humans. The rest of the DNA is found interspersed as introns in between individual genes and as repetitive sequences. The function of these short sequences is unknown, although telomeres stabilize the ends of chromosomes and centromeres allow the spindle to attach to the chromosomes during cell division. All cells, with the exception of mature mammalian erythrocytes, possess a nucleus that contains the chromosomes. The nucleus is separated from the cytoplasm by a nuclear envelope  consisting of outer and inner nuclear mem-branes ( Figure 16.1 ). Nuclear pores in the envelope ( Figure 16.1 (B) ...

  PLASMA MEMBRANE DISORDERS Numerous clinical conditions are associated with defective receptors of the plasma membrane and/or subsequent defective signal transduction or defec-tive transport of materials across the membrane. Defects of receptor proteins and signal transduction can result in the development of cancerous states , while cases of type 2 diabetes are associated with an ineffec-tive insulin receptor . Familial hypercholesterolemia, which was described, arises from defective receptors for LDL particles. The rare Tangier disease mentioned is caused by mutations in the gene for cholesterol transport protein of the plasma membrane. This protein is one of a group of transporters called ATP-binding cassette (ABC) proteins. These are multidomain structures: all have two cytosolic ATP-bind-ing domains or cassettes and two transmembrane domains each consisting of several helices. However, the most studied of the ABC transporters is the transmembrane conductance regulator protein...

  CYSTIC FIBROSIS Cystic fibrosis (CF) is a multisystem, inherited disorder characterized by the secretion of very viscous mucus secretions in the lungs, digestive tract and associated organs, and epididymis. This results in chronic respiratory disease, malabsorption, cirrhosis and electrolyte disturbances. The clinical features of CF are shown in  Table 16.1 . Cystic fibrosis is the commonest fatal, homozygous recessive disorder of the Caucasian population affecting about one in 2000 people in the UK, with one in 20 Caucasians carrying one copy of the mutated gene. The prevalence of CF varies throughout the world with certain populations reporting higher incidences. The onset may be at birth or later in childhood. Cystic fibrosis is characterized by decreased permeability of the apical membrane of epi-thelial tissues lining the lungs and other organs to chloride ions (Cl – ) that results from mutations in the  CFTR  gene that encodes the cystic fibrosis transmembran...

  MITOCHONDRIAL DISORDERS M itochondria are organelles found in almost all eukaryotic cells although numbers vary from one to several hundred per cell. They are bounded by a mitochondrial envelope that consists of outer and inner mitochondrial membranes with infoldings called cristae, and encloses a central region called the mitochondrial matrix ( Figure 16.6 ). The inner mitochondrial membrane contains five protein complexes ( Table 16.2 ) that together with cytochrome  c  perform the energy transduction reactions with the formation of ATP byoxidative phosphorylation. The matrix contains enzymes that catabolize fuel molecules to yield the reduced coenzymes NADH and FADH 2  necessary for oxidative phosphorylation, and produces small organic molecules that are the precursors in biosynthetic metabolism. The mitochondria also help in maintaining the intracellular homeostasis of many metabolites and ions, including Ca 2+  and H + . Mitochondria are also involved in ...

  CAUSES OF MITOCHONDRIAL DISORDERS Mitochondrial disorders are a heterogeneous group of disorders resulting from impairment of the mitochondrial oxidative phosphorylation system. They are associated not only with numerous mutations of the mtDNA but also mutations in nuclear genes that affect processes such as the assembly of protein subunits and the import of proteins from the cytosol into the mitochondrion. Such mutations can affect the morphology of the mitochondrion ( Figure 16.8 ). Mitochondria replicate by simple divisions that are independent of mitosis and meiosis. The mitochondrial chromosomes are copied prior to replication. However, the replicating enzyme, mtDNA-dependent DNA polymerase or DNA polymerase  F , replicates DNA with much poorer fidelity than the nuclear DNA polymerases. Thus the mutation rates of mitochondrial genes are esti-mated to be about 10 times greater than those of nuclear genes. This may contribute to the aging process . Furthermore, the mitoch...

  DIAGNOSIS AND TREATMENT OF MITOCHONDRIAL DISORDERS Considerable advances have been made in our understanding of the pathol-ogy of mitochondrial disorders. However, the diagnosis and detection of mtDNA mutations is problematic because of the varied etiology and clinical features of these diseases ( Table 16.3 ). Similarly, predictors of disease progres-sion are also highly unsatisfactory. The concentrations of lactate in plasma, cerebrospinal fluid and urine may, individually or collectively, be increased relative to normal, although these changes are also seen in numerous other clinical conditions. However, a plasma lactate : pyruvate ratio of greater than 40 is usually considered a significant indicator of mitochondrial dysfunc-tion in adults. Other indicators may be the presence of organic acids and myoglobin in the urine, ketoacidosis , and impaired renal, liver and glandular functions. It would appear that several different approaches to treating and managing mitochondrial di...

  PEROXISOMAL DISORDERS Peroxisomes ( Figure 16.10 ) are organelles surrounded by a single membrane, that carry out certain oxidation reactions, particularly those involved in the partial degradation of long chain fatty acids. Unlike mitochondria, these oxidations are not coupled to the formation of ATP. Peroxisomal proteins are synthesized in the cytosol and imported into the organelles by a com-plex process that relies upon the relevant protein possessing a peroxisomal targeting signal (PTS). The major signal (PTS1) consists of the carboxyl ter-minal three amino acid residues being the consensus sequence –Ser-Lys-Leu-COO – . Defects in peroxisomes produce a variety of lethal human diseases. The most common of these are adrenoleukodystrophy (ALD), Zellweger syndrome and Refsum’s disease. These diseases are caused by defects in individual peroxisomal enzymes or faults in the transport system necessary to convey proteins from their site of synthesis in the cytosol to the peroxisome....