RESUMEN
We report on two prenatal ultrasound diagnoses of left ventricular non-compaction cardiomyopathy (LVNC) associated with mutation of the cardiac ß-myosin heavy chain gene (MYH7). LVNC is characterized by a trabecular meshwork and deep intertrabecular myocardial recesses communicating with the left ventricular cavity. Clinical features range from non-penetrant disease in adult carriers to heart failure, arrhythmia and thromboembolism. Both cases showed cardiomegaly on prenatal ultrasound examinations, with features indicating non-compaction of the myocardium apparent in the third trimester. Mutations in the MYH7 gene were identified postnatally in each case in both the proband and the father. One infant underwent surgical mitral valvuloplasty and a mechanical valve implant later; in the other, left ventricular function was unimpaired at birth. Cardiac function in both cases remained stable at last follow-up. These cases highlight the importance of prenatal ultrasound diagnosis of LVNC and the need for cardiologic and molecular testing of first-degree relatives who may be unknown carriers of an MYH7 mutation.
Asunto(s)
Miosinas Cardíacas/genética , Enfermedades Fetales/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/genética , Cadenas Pesadas de Miosina/genética , Miosinas Ventriculares/genética , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Ventrículos Cardíacos/anomalías , Ventrículos Cardíacos/cirugía , Humanos , Lactante , Recién Nacido , No Compactación Aislada del Miocardio Ventricular/cirugía , Masculino , Mutación , Embarazo , Diagnóstico Prenatal , Resultado del Tratamiento , Ultrasonografía PrenatalRESUMEN
Hirschsprung disease (HSCR) or colonic aganglionosis is a congenital disorder characterized by an absence of intramural ganglia along variable lengths of the colon resulting in intestinal obstruction. The incidence of HSCR is 1 in 5,000 live births. Mutations in the RET gene, which codes for a receptor tyrosine kinase, and in EDNRB which codes for the endothelin-B receptor, have been shown to be associated with HSCR in humans. The lethal-spotted mouse which has pigment abnormalities, but also colonic aganglionosis, carries a mutation in the gene coding for endothelin 3 (Edn3), the ligand for the receptor protein encoded by EDNRB. Here, we describe a mutation of the human gene for endothelin 3 (EDN3), homozygously present in a patient with a combined Waardenburg syndrome type 2 (WS2) and HSCR phenotype (Shah-Waardenburg syndrome). The mutation, Cys159Phe, in exon 3 in the ET-3 like domain of EDN3, presumably affects the proteolytic processing of the preproendothelin to the mature peptide EDN3. The patient's parents were first cousins. A previous child in this family had been diagnosed with a similar combination of HSCR, depigmentation and deafness. Depigmentation and deafness were present in other relatives. Moreover, we present a further indication for the involvement of EDNRB in HSCR by reporting a novel mutation detected in one of 40 unselected HSCR patients.
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Endotelinas/genética , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/genética , Mutación , Síndrome de Waardenburg/complicaciones , Síndrome de Waardenburg/genética , Secuencia de Aminoácidos , Secuencia de Bases , ADN/genética , Cartilla de ADN/genética , Femenino , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Síndrome de Waardenburg/clasificaciónRESUMEN
OBJECTIVE: Li Fraumeni syndrome (LFS) and Von Hippel-Lindau disease (VHL) are two rare hereditary tumor syndromes, characterized by a high risk of developing multiple tumors at various sites and ages for which preventive and treatment options are limited. For partners, it may be difficult to deal with the on-going threat of tumors in both their spouse and children. Therefore, this study aims to evaluate the prevalence of and factors associated with psychological distress among partners of individuals with or at high risk of LFS or VHL. METHODS: As part of a nationwide, cross-sectional study, partners of individuals diagnosed with or at high risk of LFS or VHL were invited to complete a self-report questionnaire assessing distress, worries, and health-related quality of life. RESULTS: Fifty-five (58%) of those high-risk individuals with a partner consented to having their partner approached for the study. In total, 50 partners (91%) completed the questionnaire, of whom 28% reported clinically relevant levels of syndrome-related distress. Levels of distress and worries of the partners and their high-risk spouse were significantly correlated. Younger age and a lack of social support were also associated significantly with heightened levels of distress and worries. The majority of partners (76%) believed that professional psychosocial support should be routinely offered to them. CONCLUSIONS: Approximately one-quarter of the partners exhibit clinically relevant levels of distress that warrant psychological support. The distress levels of the 'patient' could potentially be used to identify partners at risk of developing clinically relevant levels of distress.
Asunto(s)
Adaptación Psicológica , Trastornos de Adaptación/psicología , Trastornos de Ansiedad/psicología , Trastorno Depresivo/diagnóstico , Predisposición Genética a la Enfermedad/psicología , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/psicología , Esposos/psicología , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/psicología , Trastornos de Adaptación/diagnóstico , Trastornos de Adaptación/epidemiología , Adulto , Anciano , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/epidemiología , Estudios Transversales , Trastorno Depresivo/epidemiología , Trastorno Depresivo/psicología , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven , Enfermedad de von Hippel-Lindau/genéticaRESUMEN
Von Hippel-Lindau disease (VHL) is a hereditary tumor susceptibility syndrome, characterized by an increased risk of developing multiple benign and malignant tumors at various sites and ages with limited preventive options. This study evaluates the prevalence of distress among VHL family members and factors associated significantly with such distress. Forty-eight families with a VHL mutation were identified via the nine family cancer clinics in the Netherlands. In total, 171 family members (carriers, 50% at-risk, non-carriers) were approached, of whom 123 (72%) completed a self-report questionnaire. Approximately 40% of the VHL family members reported clinically relevant levels of distress, approaching 50% among the carriers and, possibly even more striking, 36% among the non-carriers. Having lost a first degree relative due to VHL during adolescence (OR 11.2; 95% CI 1.4-86.9) was related significantly to heightened levels of distress. Approximately, only one-third of those who reported heightened levels of distress had received professional psychosocial support. A substantial percentage of family members experience clinically relevant levels of distress. We would recommend the introduction of a procedure for screening for distress in this vulnerable population. Special attention should be paid to those individuals who have lost a close relative due to VHL during adolescence.
Asunto(s)
Enfermedad de von Hippel-Lindau/psicología , Adulto , Femenino , Humanos , Modelos Logísticos , Masculino , Calidad de Vida , Apoyo Social , Encuestas y CuestionariosRESUMEN
Abdominal aortic aneurysms (AAA), are usually asymptomatic until rupture causes fatal bleeding, posing a major vascular health problem. AAAs are associated with advanced age, male gender, and cardiovascular risk factors (e.g. hypertension and smoking). Strikingly, AAA and AOD (arterial occlusive disease) patients have a similar atherosclerotic burden, yet develop either arterial dilatation or occlusion, respectively. The molecular mechanisms underlying this diversion are yet unknown. As this knowledge could improve AAA treatment strategies, we aimed to identify genes and signaling pathways involved. We compared RNA expression profiles of abdominal aortic AAA and AOD patient samples. Based on differential gene expression profiles, we selected a gene set that could serve as blood biomarker or as pharmacological intervention target for AAA. In this AAA gene list we identified previously AAA-associated genes COL11A1, ADIPOQ, and LPL, thus validating our approach as well as novel genes; CXCL13, SLC7A5, FDC-SP not previously linked to aneurysmal disease. Pathway analysis revealed overrepresentation of significantly altered immune-related pathways between AAA and AOD. Additionally, we found bone morphogenetic protein (BMP) signaling inhibition simultaneous with activation of transforming growth factor ß (TGF-ß) signaling associated with AAA. Concluding our gene expression profiling approach identifies novel genes and an interplay between BMP and TGF-ß signaling regulation specifically for AAA.
RESUMEN
Hypertrophic cardiomyopathy (HCM) is a disease characterised by unexplained left ventricular hypertrophy (LVH) (i.e. LVH in the absence of another cardiac or systemic disease that could produce a similar degree of hypertrophy), electrical instability and sudden death (SD).Germline mutations in genes encoding for sarcomere proteins are found in more than half of the cases of unexplained LVH. The autosomal dominant inherited forms of HCM are characterised by incomplete penetrance and variability in clinical and echocardiographic features, prognosis and therapeutic modalities. The identification of the genetic defect in one of the HCM genes allows accurate presymptomatic detection of mutation carriers in a family. Cardiac evaluation of at-risk relatives enables early diagnosis and identification of those patients at high risk for SD, which can be the first manifestation of the disease in asymptomatic persons.In this article we present our experience with genetic testing and cardiac screening in our HCM population and give an overview of the current literature available on this subject. (Neth Heart J 2007;15:184-9.).
RESUMEN
In animal societies, conflicts can be resolved by combatants or through third-party intervention. In gregarious species, conflicts among pairs can spread to involve multiple individuals. In the case of large conflicts, containment and termination of aggression by third parties is important. Successful intervention relies on consensus among combatants about the intervener's capacity to use force. We refer to this consensus as power. We measure it and study how it arises, using as our model system a pigtailed macaque (Macaca nemestrina) society. In macaques, the degree to which one individual perceives another as capable of using force is communicated using a special dominance signal. Group consensus about an individual's capacity to use force arises from the network of signaling interactions. We derive a formalism to quantify consensus in the network. We find that the power distribution is fat tailed and power is a strong predictor of social variables including request for support, intervention cost, and intensity. We develop models to show how dominance-signaling strategies promote robust power distributions despite individual signaling errors. We suggest that when considering correlated interactions among many individuals it can be more useful to emphasize coarse-grained information stored at the group level--behavioral macrostates--over detailed information at the individual level.
Asunto(s)
Comunicación Animal , Macaca nemestrina/fisiología , Animales , Modelos Biológicos , Predominio SocialRESUMEN
We present a theoretical framework within which to analyze the results of experimental evolution. Rapidly evolving organisms such as viruses, bacteria, and protozoa can be induced to adapt to laboratory conditions on very short human time scales. Artificial adaptive radiation is characterized by a list of common observations; we offer a framework in which many of these repeated questions and patterns can be characterized analytically. We allow for stochasticity by including rare mutations and bottleneck effects, demonstrating how these increase variability in the evolutionary trajectory. When the product Np, the population size times the per locus error rate, is small, the rate of evolution is limited by the chance occurrence of beneficial mutations; when Np is large and selective pressure is strong, the rate-limiting step is the waiting time while existing beneficial mutations sweep through the population. We derive the rate of divergence (substitution rate) and rate of fitness increase for the case when Np is large and illustrate our approach with an application to an experimental data set. A minimal assumption of independent additive fitness contributions provides a good fit to the experimental evolution of the bacteriophage phiX174.
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Evolución Biológica , Evolución Molecular Dirigida , Modelos Genéticos , Modelos Estadísticos , Animales , Bacterias/genética , Eucariontes/genética , Mutación , Procesos Estocásticos , Virus/genéticaRESUMEN
When the same sequence of nucleotides codes for regions of more than one functional polypeptide, this sequence contains overlapping genes. Overlap is most common in rapidly evolving genomes with high mutation rates such as viruses, bacteria, and mitochondria. Overlap is thought to be important as: (1) a means of compressing a maximum amount of information into short sequences of structural genes; and (2) as a mechanism for regulating gene expression through translational coupling of functionally related polypeptides. The stability of overlapping codes is examined in relation to the information cost of overlap and the mutation rate of the genome. The degree of overlap in a given population will tend to become monomorphic. Evolution toward partial overlap of genes is shown to depend on a convex cost function of overlap. Overlap does not evolve when expression of overlapping genes is mutually exclusive and produced by rare mutations to the wild-type genome. Assuming overlap increases coupling between functionally related genes, the conditions favoring overlap are explored in relation to the kinetics of gene activation and decay. Coupling is most effective for genes in which the gene overlapping at its 5' end (leading gene) decays rapidly, while the gene overlapping at the 3' end (induced gene) decays slowly. If gene expression can feedback on itself (autocatalysis), then high rates of activation favor overlap.
Asunto(s)
Evolución Molecular , Genes Sobrepuestos/genética , Modelos Genéticos , Modelos Teóricos , Regulación de la Expresión Génica , Selección Genética , Activación TranscripcionalRESUMEN
Clinicians have long suspected an association of classic amyotrophic lateral sclerosis (ALS) with Parkinson's disease (PD), dementia, or both. If proven, this would raise the possibility of a shared genetic susceptibility to the three disorders. To investigate this hypothesis, we compared 151 newly diagnosed ALS patients (seven familial) with 140 controls in terms of cumulative incidence of ALS, PD, and dementia in parents, siblings, and grandparents. We used Cox proportional hazards analysis to compute rate ratios (RRs) for ALS, dementia, and PD in relatives of ALS patients versus relatives of controls. The risk for dementia was significantly higher in relatives of ALS patients than in those of controls (RR = 1.9; 95% CI 1.1-3.1) and was similar for relatives of patients with sporadic and familial ALS. The risk of PD was higher in relatives of patients with familial ALS (RR = 5.6; 95% CI 0.6-50.3) than in relatives of patients with sporadic ALS (RR = 1.8; 95% CI 0.5-6.0), but these differences were not statistically significant, probably due to insufficient statistical power with the available sample size. These findings indicate that ALS and dementia, and perhaps also PD, co-occur within families more often than expected by chance, suggesting that there may be a shared genetic susceptibility to these disorders.
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Esclerosis Amiotrófica Lateral/genética , Demencia/genética , Enfermedad de Parkinson/genética , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/epidemiología , Demencia/complicaciones , Demencia/epidemiología , Susceptibilidad a Enfermedades , Métodos Epidemiológicos , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Riesgo , Análisis de SupervivenciaRESUMEN
A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1) to estimate the frequency of electrocardiographic (ECG) and echocardiographic abnormalities; (2) to establish the proportion of carriers with dilated cardiomyopathy and (3) to assess possible associations between dilated cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers, aged 18-60 years, were traced through the files of the central register kept at the department of Human Genetics in Leiden. Investigations included full medical history, physical examination, ECG and two-dimensional and M-mode echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%, BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%, BMD 16%). Only 38% had a completely normal investigation of the heart. We found no association between genotype and cardiac manifestations. Our study underlines that cardiac involvement is part of the dystrophinopathies. Carriers should be told about the increased risk of this complication when asking genetic advice. It also implicates that a complete cardiological evaluation should be performed at least once in all carriers. If left ventricle dilatation or dilated cardiomyopathy is present a yearly follow up is needed, in order to start timely therapy.
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Corazón/fisiopatología , Heterocigoto , Distrofias Musculares/fisiopatología , Adolescente , Adulto , Estudios Transversales , Electrocardiografía , Salud de la Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distrofias Musculares/genéticaRESUMEN
Viruses from several different families are able to exploit their host's cell death programmes so as to maximize viral fitness. Consideration of the evolution of such strategies has lead to the suggestion that the virus should inhibit apoptosis, in order to prolong the life of the cell and thereby maximize the number of progeny virions. The host, on the other hand, should stimulate apoptosis thereby inhibiting viral growth and blocking viral spread. For example, the function of the latent membrane protein I (LMPI) of the Epstein-Barr virus and the bcl-2 homologue gene A179L of African swine fever virus is to inhibit apoptosis. However, in other cases it is the virus that stimulates cell death or the host that benefits from inhibiting apoptosis, such as in fatal alphavirus encephalitis. This has been explained by assuming that virus-induced apoptosis in non-regenerating cells would be detrimental to the host. We present a mathematical framework for understanding virus-induced apoptosis which accounts for these two opposite solutions to virus infection with respect to the mode of virus replication and the life cycle of the target cell.
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Apoptosis , Cómputos Matemáticos , Modelos Biológicos , Replicación Viral , Evolución Biológica , Herpesvirus Humano 1/fisiología , Herpesvirus Humano 4/fisiología , Humanos , Nucleopoliedrovirus/fisiología , Virus Sindbis/fisiologíaRESUMEN
The progress of HIV is accompanied by the infection and decline of the population of CD4+ cells. This reduction in cells results from both cytolytic influences of the virus and virus-specific cytotoxic T-cell (CTL) responses. We seek to characterize the extent of CD4+ reduction caused by HIV-specific CTLs at equilibrium. Here we show that intermediate levels of cytotoxic killing of infected cells can be inferior to both strong and weak or absent immune responses. We further show that the deleterious effects of the CTL response are made worse by a slow immune response. Bystander effects in which uninfected cells are thought to be eliminated by non-specific CTL activation lead to small or negligible reductions in uninfected CD4+ cells. Latently infected cells containing pro-viral DNA and which become activated at a constant rate ensure that the immune response is more effective for a larger range of CTL activities and reduces T-cell associated pathology.
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Linfocitos T CD4-Positivos/inmunología , VIH/inmunología , Linfocitos T Citotóxicos/inmunología , Apoptosis , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/virología , VIH/patogenicidad , VIH/fisiología , Humanos , Modelos Inmunológicos , Linfocitos T Citotóxicos/virología , Latencia del VirusRESUMEN
An important component of the latency period of the transmissible spongiform encephalopathies (prion diseases) can be attributed to delays during the propagation of the infectious prion isoform, PrPSc, through peripheral nervous tissues. A growing body of data report that the host prion protein, PrPC, is required in both peripheral and central nervous tissues for susceptibility to infection. We introduce a mathematical model, which treats the PrPSc as a mobile infectious pathogen, and show how peripheral delays can be understood in terms of the intercellular dispersal properties of the PrPSc strain, its decay rate, and its efficiency at transforming the PrPC. It has been observed that when two pathogenic strains co-infect a host, the presence of the first inoculated strain can slow down, or stop completely, the spread of the second strain. This is thought to result from a reduced concentration of host protein available for conversion by the second strain. Our model can explain the mechanisms of such interstrain competition and the time-course of the increased delay. The model provides a link between those data suggesting a role for a continuous chain of PrP-expressing tissue linking peripheral sites to the brain, and data on prion strain competition.
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Modelos Biológicos , Enfermedades por Prión/transmisión , Animales , Humanos , Proteínas PrPC/patogenicidad , Proteínas PrPSc/patogenicidadRESUMEN
On the evolutionary trajectory that led to human language there must have been a transition from a fairly limited to an essentially unlimited communication system. The structure of modern human languages reveals at least two steps that are required for such a transition: in all languages (i) a small number of phonemes are used to generate a large number of words; and (ii) a large number of words are used to a produce an unlimited number of sentences. The first (and simpler) step is the topic of the current paper. We study the evolution of communication in the presence of errors and show that this limits the number of objects (or concepts) that can be described by a simple communication system. The evolutionary optimum is achieved by using only a small number of signals to describe a few valuable concepts. Adding more signals does not increase the fitness of a language. This represents an error limit for the evolution of communication. We show that this error limit can be overcome by combining signals (phonemes) into words. The transition from an analogue to a digital system was a necessary step toward the evolution of human language.
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Evolución Biológica , Lenguaje , Modelos Teóricos , HumanosRESUMEN
A new polymorphic DNA marker RN1, defining locus DXS369, was recently isolated. Using different somatic cell hybrids, RN1 was mapped between markers 4D-8 and U6.2. We have narrowed the localization of RN1 to the region between 4D-8 and FRAXA by genetic mapping in fragile X [fra(X)] families. Combined with information from other reports, the following order of loci on Xq27-q28 is suggested: cen-F9-(DXS105-DXS152)-DXS98-DXS369-FRAXA- DXS304-(DXS52-DXS15-F8)-tel. The locus DXS369 is closely linked to FRAXA, with a peak lodscore of 18.5 at a recombination fraction of 0.05. Therefore, RN1 is a useful probe for carrier detection and prenatal diagnosis in fra(X) families.
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Sondas de ADN/genética , Síndrome del Cromosoma X Frágil/genética , Polimorfismo de Longitud del Fragmento de Restricción , Cromosoma X , Animales , Mapeo Cromosómico , Síndrome del Cromosoma X Frágil/diagnóstico , Tamización de Portadores Genéticos , Humanos , Células Híbridas , Linaje , Diagnóstico PrenatalRESUMEN
Microcephaly, intrauterine growth retardation, a hellenic nose, and severe micrognathia were diagnosed as a form of bird-headed dwarfism (Seckel-like) syndrome in a female infant. In the subsequent pregnancy, monitored by serial ultrasound examinations, severe growth retardation was established at 17 and 20 weeks of pregnancy. The head circumference was disproportionately small in relation to the abdominal circumference and enabled the diagnosis of microcephaly. There was also extreme micrognathia. The pregnancy was terminated, and the diagnosis of a Seckel-like syndrome of bird-headed dwarfism was confirmed at autopsy of the male fetus. This variant of bird-headed dwarfism has probably autosomal recessive inheritance. Ultrasonic assessment of the facial area together with the measurements of fetal head and abdominal circumference are essential in the early prenatal diagnosis of this syndrome in pregnancies of reliably established duration.
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Anomalías Múltiples/genética , Retardo del Crecimiento Fetal/genética , Microcefalia/genética , Micrognatismo/genética , Anomalías Múltiples/diagnóstico , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Genes Recesivos , Humanos , Masculino , Microcefalia/diagnóstico , Micrognatismo/diagnóstico , Embarazo , Diagnóstico Prenatal , Síndrome , UltrasonografíaRESUMEN
The intragenic (FMR-1) probe pE5.1 was used for DNA analysis in fragile X families. With this probe fragments of altered size can be detected in female carriers, affected individuals and transmitting males. The length of the altered fragments was found to vary from one generation to another as well as between sibs. This instability of the DNA detected by pE5.1 was also seen in peripheral blood within single individuals. These phenomena are illustrated by 4 exemplary families segregating the fragile X syndrome. We demonstrate the diagnostic contribution of intragenic analysis to carrier detection as well as the identification of normal transmitting males carrying premutations. One of the families illustrates the passage of a premutation to a male through 2 generations.
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Sondas de ADN , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , ADN/genética , Análisis Mutacional de ADN , Femenino , Expresión Génica , Tamización de Portadores Genéticos , Humanos , Masculino , Linaje , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
We examined ten patients from three families with von Hippel-Lindau disease and 26 of their at-risk relatives for the presence of twin vessels, defined as a paired retinal arteriole and venule that are separated by less than the diameter of one venule and extend for a distance of more than one disk diameter. They were compared with 36 age- and sex-matched controls. Of the 36 subjects in the study group, 23 had twin vessels compared with two controls (P less than 10(-6). Of the ten patients, nine (14 eyes) had twin vessels; no twin vessels were found in their controls (P = 5.9 x 10(-5)). Fourteen at-risk relatives and two of their controls had twin vessels (P = 9.4 x 10(-4)).
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Angiomatosis/genética , Neoplasias del Ojo/genética , Retina/patología , Vasos Retinianos/patología , Adulto , Angiomatosis/patología , Neoplasias del Ojo/patología , Femenino , Angiografía con Fluoresceína , Fondo de Ojo , Humanos , Masculino , Persona de Mediana Edad , Oftalmoscopía , Linaje , Vasos Retinianos/anomalías , Factores de RiesgoRESUMEN
Advanced tumor growth requires the formation of new blood vessels (angiogenesis). Whether new blood vessels are formed or not depends on a balance between angiogenesis inhibitors and promoters. Host tissue, as well as tumor cells, express inhibitory factors preventing angiogenesis. During cancer progression, tumor cell lines evolve which produce factors promoting the angiogenic switch. We use mathematical models in order to examine the conditions required for angiogenic cell lines to emerge and hence for the disease to progress. We find that genetic instability, defined as a much elevated mutation rate of somatic cells, is required for the emergence of angiogenic tumor cells. This is because a high mutation rate ensures that within a short period of time, a sufficiently high number of angiogenic cells are generated. This founder population of mutant cells is large enough to overcome the inhibitory factors produced by the tissue thereby inducing the angiogenic switch through the production of promoters. In the absence of genetic instability, angiogenic cells cannot fix, even if the relevant mutations are generated at low levels in the tumor cell population. This is because angiogenic promoters will not be sufficiently abundant to counter the influence of inhibitory factors. In this context, the inhibition of angiogenesis can be viewed as a host defense ensuring that the tumor need be genetically unstable if it is to grow and progress beyond a certain size limit. We observe that genetic instability is of value early in tumorigenesis but becomes a liability later. This is because instability decreases the fitness of the angiogenic tumor once it has become established.