Genética Humana e Embriologia

The Ductus Arteriosus (DA) is a normal and essential fetal structure that connects the main pulmonary artery and the descending aorta. The DA constriction which occurs immediately after birth is triggered by: (a) an increase in oxygen tension, (b) a dramatic decline in circulating PGE2 and a promotion of its degradation in the lung, (c) a decrease in the expression of PGE receptors in the DA wall and (d) a decrease in blood pressure within the DA. Ion channels play an essential role in this acute response that is known as functional DA closure. Oxygenation from fetal to neonatal circulation inhibits several potassium channels (voltage-dependent and ATP-dependent), which then leads to membrane depolarization. This depolarization triggers the activation of voltage-dependent calcium channels, and extracellular calcium then enters into the cytosol of smooth muscle cells of the DA. Calcium is also released from the sarcoplasmic reticulum, with a consequent supply provided through store-operated calcium channels. An increase in cytosolic calcium induces DA constriction. Ion channels also play a role in vascular remodelling of the DA, although this has not yet been extensively investigated. Voltage-dependent L- and T-type calcium channels promote formation of intimal thickening through an increase in proliferation and migration of DA smooth muscle cells. Current medical treatment for patients with persistent patent DA is limited to cyclooxygenase inhibitors such as indomethacin and ibuprofen. A better understanding of the role of ion channels in vasoconstriction and vascular remodelling of the DA may encourage the design and development of novel pharmacological treatments for patients with patent ductus arteriosus. In this review, we focus on current knowledge on the roles of ion channels in the DA.

Turner syndrome is a chromosomal disorder characterized by the presence of a single normal X chromosome in women. Additionally to the X chromosome monosomy, other cell lines can co-exist, containing the Y chromosome or part of it. The presence of Y chromosome in patients with Turner syndrome represents an increased risk (15- 30%) of developing gonadoblastoma. In this study we screened for the absence/presence of four genes mapped on Y chromosome (SRY, TSPY, DDX3Y and HSFY) in 98 female samples obtained from different tissues, namely peripheral blood, amniotic fluid, gonadal tissue and miscarriages samples, previously characterized cytogenetically having at least one cell line with monosomy X or an abnormal X chromosome. We also evaluate the importance of a molecular test for detection of Y chromosome sequences using a combination of conventional cytogenetic methods and DNA analysis. Three miscarriages and one gonadal tissue presented Y-chromosome DNA sequences out of the 98 studied samples. We have discussed the higher frequency of the Y sequences in spontaneous abortions with 45, X karyotype and we have advised the detection of Y-chromosome material in Turner patients in order to improve the clinical orientation and the consequent prognosis.

Hypertrophic cardiomyopathy (HCM) is caused by a dominant mutation of the sarcomere protein gene in approximately 60% of cases. Genetic testing of HCM has several benefits. Diagnosis can be confirmed if the sarcomere protein gene mutation is identified. Genetic testing enables to follow-up blood relatives who are mutationpositive only, and can identify asymptomatic and non-onset patients. Relatives with negative results of genetic testing could be freed from anguish. On the other hand, genetic testing has some disadvantages. Treatment often does not change after testing. Forty percent of cases has unknown causative genes. Relationship between gene mutation and clinical findings or treatment responsiveness is little known, and so on. Many issues need to be resolved to incorporate genetic diagnosis into daily practice for HCM. However, genetic testing for HCM cannot be regarded as unnecessary and expensive debauchery, but rather represents a valuable measure in the medical facilities. Although there still remain questions about genetic diagnosis of HCM, accumulated knowledge to date is fairly enough to establish the genetic testing as a useful tool for individualized management of HCM patients and their families.

In this article, an attempt to incorporate recent knowledge of epigenetics into the evolutionary theory is presented. As our interest is to clarify evolutionary mechanisms at the molecular level and to connect them to phenotype evolution, the interplay of drift and selection (near-neutrality) on molecular evolution is briefly reviewed. Epigenetic phenomena are partly controlled by genetic systems via chromatin structure, and special attention has been paid to the dynamic evolution of three gene families which encode chromatin components. These gene families are characterized by rapid birth and death of gene copy members, and weak diversity enhancing selection. Also the protein products contain disordered domain that provides flexible chromatin structure. The near-neutrality concept may be extended to their evolution. Here drift, selection and epigenetics become inseparable, and their interplay is thought to have been needed for the evolution of complex gene regulatory systems.