Catálogo de publicaciones - libros

Diabetes mellitus is characterized by fasting and postprandial hyperglycemia. Type 1 diabetes occurs secondary to autoimmune destruction of the insulin-secreting pancreatic β-cells, whereas type 2 diabetes results from a deficiency of insulin action secondary to a combination of insulin resistance and relative β-cell dysfunction. Familial clustering of type 1 and 2 diabetes has suggested a genetic contribution to the etiology of the diseases, but monozygotic twin and other studies have indicated that environmental factors also contribute to their etiology. Although relatively rare monogenic forms of diabetes have been described, type 1 and 2 diabetes are, in general, complex, polygenic diseases.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combined occurrence of tumors of the parathyroids, pancreatic islets, and anterior pituitary. In addition, some patients may also develop adrenal cortical, carcinoid, facial angiofibromas, collageno-mas, and lipomatons tumors. MEN1 is inherited as an autosomal-dominant disorder and the gene causing MEN1 is located on chromosome 11q13. The MEN1 gene consists of 10 exons that encode a 610 amino acid protein, menin, which has a role in transcriptional regulation and genome stability. The mutations causing MEN1 are of diverse types and are scattered throughout the coding region. Mice deleted for a MEN1 allele develop endocrine tumors similar to those found in MEN1 patients. The availability of these mouse models for MEN1 will help to further elucidate the role of menin in regulating cell proliferation.

The pathophysiological consequences of kidney failure and other catabolic conditions such as diabetes, burn injury, cancer, sepsis, muscle denervation and starvation, include loss of protein stores. This chapter will describe the impressive concordance between studies performed with cultured muscle cells and studies involving experimental animals and patients suggests that there is strong evolutionary pressure to maintain these “stress”-related responses. Understanding the mechanisms leading to activation of transcription could lead to improved methods of preventing the loss of muscle protein.

Molecular genetic analysis of the demyelinating neuropathies Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies has uncovered a novel mutational mechanism whereby a reciprocal recombination involving a misaligned flanking repeat sequence results in both the Charcot-Marie-Tooth disease type-1A duplication and hereditary neuropathy with liability to pressure palsies deletion. These studies have illuminated the role that gene dosage may play in causing a disease phenotype, which has important implications for therapeutic strategies, and which may underlie the basis of the extreme clinical variability. The identification of these rearrangement mutations (duplication and deletion) has resulted in the availability of molecular procedures for establishing or excluding a secure diagnosis, enabling presymptomatic and prenatal diagnosis, and providing prognostic information.

Expansion of trinucleotide repeat sequences is the mutational mechanism in at least 16 neurological disorders, including fragile X type A syndrome, myotonic dystrophy, spinobulbar muscular atrophy, Huntington disease, and several others. The discovery of trinucleotide repeat expansions provides a biological explanation for “anticipation,”the increase in disease severity and decrease in age of onset from one generation to the next, observed in all of these disorders. This chapter provides an overview of trinucleotide repeat disorders and discusses some of the findings in pathogenesis studies.

Alzheimer’s Disease (AD), Lewy body variant of AD, and the frontotemporal dementias are the three most common causes of adult onset dementia. This chapter will examine the genetic basis of AD and Lewy body variant, familial British dementia and familial encephalopathy with neuronal dementia with neuroserpin deposits, tau mutations in FTDP-17, and the practical implications of genetic testing.