Reduced Penetrance and Variable Expression of SCN5A Mutations and the Importance of Co-inherited Genetic Variants: Case Report and Review of the Literature.

Mutations in the SCN5A gene are responsible for multiple phenotypical presentations including Brugada syndrome, long QT syndrome, progressive familial heart block, sick sinus syndrome, dilated cardiomyopathy, lone atrial fibrillation and multiple overlap syndromes. These different phenotypic expressions of a mutation in a single gene can be explained by variable expression and reduced penetrance. One of the possible explanations of these phenomena is the co-inheritance of genetic variants. We describe a family where the individuals exhibit a compound heterozygosity in the SCN5A gene including a mutation (R1632H) and a new variant (M858L). Individuals with both the mutation and new variant present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age. We give an overview of the different phenotypes of "SCN5A disease" and discuss the importance of co-inherited genetic variants in the expression of SCN5A disease.

Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration.

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.

Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome.

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.

Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.

Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin.

OBJECTIVE: To determine the prevalence of desmosomal gene mutations in athletes with complex arrhythmias (VA) of right ventricular (RV) origin and structural RV abnormalities to evaluate whether there is sufficient genetic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC) to consider them the same or different entities. DESIGN: Observational cohort SETTING: Tertiary hospital referrals PATIENTS: Forty-seven consecutive athletes (age 42 (11) years) with complex VA of RV morphology (excluding idiopathic right ventricular outflow tract ventricular tachycardia), who performed 14 (9) h/week of moderate to intense sport practise for 19 (9) years. INTERVENTIONS: Clinical evaluation (detailed sports history, multi-modality imaging, electrophysiological study) and sequencing of five candidate desmosomal genes. RESULTS: A clinical diagnosis of definite or suspected ARVC by task force criteria (TFC) was met in 24 (51%) and 17 (36%), respectively. ARVC classification was not related to the rate of major arrhythmic events (p=0.28). Pathogenic mutations (four novel) were identified in six athletes (12.8%), which is below published rates for familial ARVC (27-52%). Moreover, only two athletes had a suggestive family history. Severe RV dysfunction was more frequent in mutation carriers (33% vs 2%, p=0.04), but otherwise TFC features were similar to those without mutations. No mutations were found in the 20 athletes performing more than average weekly exercise, yet all met the criteria for definite or suspected ARVC. CONCLUSIONS: In this athletic cohort, we found lower than expected rates of desmosomal gene mutations, particularly among those performing the most exercise. This adds further weight to the hypothesis that an ARVC-like phenotype may be acquired through intense exercise without an identifiable genetic predisposition.

Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons.

Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.

Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis.

Vascular endothelial cadherin, VE-cadherin, mediates adhesion between endothelial cells and may affect vascular morphogenesis via intracellular signaling, but the nature of these signals remains unknown. Here, targeted inactivation (VEC-/-) or truncation of the beta-catenin-binding cytosolic domain (VECdeltaC/deltaC) of the VE-cadherin gene was found not to affect assembly of endothelial cells in vascular plexi, but to impair their subsequent remodeling and maturation, causing lethality at 9.5 days of gestation. Deficiency or truncation of VE-cadherin induced endothelial apoptosis and abolished transmission of the endothelial survival signal by VEGF-A to Akt kinase and Bcl2 via reduced complex formation with VEGF receptor-2, beta-catenin, and phosphoinositide 3 (PI3)-kinase. Thus, VE-cadherin/ beta-catenin signaling controls endothelial survival.

Sexualidad y relaciones de pareja en la vida de mujeres que sufrieron violación en su niñez o adolescencia / Sexuality and partner relationships in women who suffered rape during their childhood or adolescence

El objetivo de este estudio prospectivo fue investigar la sexualidad y las relaciones de parejas que establecen mujeres que sufrieron violación en su niñez y adolescencia. La población del estudio la constituyó una cohorte de 225 mujeres adolescentes cuyos embarazos fueron productos de violación y que fueron atendidas en CEMERA durante los años 1984 a 1994. A todas ellas se les aplicó una encuesta en la primera consulta. Se estudiaron variables relacionadas con sexualidad y relaciones de pareja. Los resultados corresponden a 124 mujeres que fueron localizadas y entrevistadas lo que representa el 55 por ciento de la población en estudio. Características personales y familiares: El 50 por ciento tienen entre 16 y 19 años mientras que el 40 por ciento tienen entre 20 y 30 años, un 80 por ciento son solteras, un 55 por ciento realizan labores de casa, sólo un 42 por ciento alcanzó E. Media, un 61 por ciento vive y depende de su familia de origen. Situación de pareja: Un 41 por ciento no ha establecido ningún tipo de relación afectiva con el sexo opuesto, mientras que un 17 por ciento se casó y un 14 por ciento esta conviviendo. Aspecto de sexualidad: El 52 por ciento de ellas había iniciado actividad sexual voluntaria posterior. De este porcentaje la mitad inició actividad sexual antes del año. El 63 por ciento de ellas había tenido una sola pareja sexual mientras que el 25 por ciento había tenido 2 parejas sexuales y un 12 por ciento 3 y más parejas. Un 33 por ciento de sus parejas tienen entre 30 y 57 años. El 64 por ciento de las entrevistadas indicó que su pareja supo de la violación, un 72 por ciento de los supieron reaccionaron bien y la apoyaron pero un 28 por ciento la abandonó. Es importante notar que estas mujeres encontraron parejas que más bien satisfacieron sus necesidades materiales más que las necesidades emocionales. En general ellas no tuvieron éxito en tener una relación de pareja completa, feliz en lo sexual y emocional