RESUMEN
Studies have reported a wide range of inflammatory responses in the nerve, skin and plasma of leprosy patients. The expression levels of each biomolecule was individualistic, however could be categorized as high and low based on their statistical mean level. Here we report for the first time, expression of a set of biomolecules relating with each other in a defined proportion. The hypothesis of this paper is that the segregation of high and low combinations of a set of biomolecules follows either classical Mendelian dihybrid ratio or epistatic ratios. This hypothesis was tested for 17 molecules in three tissues; nerve, skin and plasma and were confirmed to interact in 9:7, 9:3:4, 12:3:1, 13:3, 15:1 epistatic proportions. These findings suggest that there could be a significant role of networking of molecules in defined epistatic proportions and could be important in pathophysiology of peripheral nerve.
Asunto(s)
Epistasis Genética , Inflamación/genética , Lepra/patología , Algoritmos , Antígenos Bacterianos/inmunología , Genes Recesivos , Humanos , Inflamación/inmunología , Lepra/genética , Lepra/inmunología , Modelos Genéticos , Modelos Estadísticos , Neuronas/metabolismo , Nervios Periféricos/fisiopatología , Fenotipo , Plasma/metabolismo , Estudios Retrospectivos , Piel/metabolismo , Resultado del TratamientoRESUMEN
OBJECTIVES: Netherton's syndrome (NS) is a rare autosomal recessive condition, first described in 1958, which involves a complex immunological dysfunction, ichthyosiform dermatitis, and erythroderma, characteristic defects of the hair shaft and atopy. Recurrent bacterial infection in the skin of patients with NS is frequent. METHODS: This paper represents the first case report of leprosy and concurrent NS. DISCUSSION: This case merits discussion among doctors in endemic and non-endemic areas to evaluate the chronic use of systemic corticosteroids as a risk factor for leprosy. The present patient came from an endemic area of leprosy and was treated chronically with systemic corticosteroids for erythroderma. This treatment, along with the immunodeficiency related to the syndrome and caused by a genetic mutation in SPINK5, may be a facilitating factor for the infection.
Asunto(s)
Lepra Lepromatosa/complicaciones , Lepra Lepromatosa/genética , Síndrome de Netherton/complicaciones , Síndrome de Netherton/genética , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Adulto , Brasil , Genes Recesivos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Inhibidor de Serinpeptidasas Tipo Kazal-5RESUMEN
The epidemiology of leprosy is characterized by heterogeneity in susceptibility and clustering of disease within households. We aim to assess the extent to which different mechanisms for heterogeneity in leprosy susceptibility can explain household clustering as observed in a large study among contacts of leprosy patients.We used a microsimulation model, parameterizing it with data from over 20,000 contacts of leprosy patients in Bangladesh. We simulated six mechanisms producing heterogeneity in susceptibility: (1) susceptibility was allocated at random to persons (i.e. no additional mechanism), (2) a household factor, (3, 4) a genetic factor (dominant or recessive), or (5, 6) half a household factor and half genetic. We further assumed that a fraction of 5%, 10%, and 20% of the population was susceptible, leading to a total of 18 scenarios to be fitted to the data. We obtained an acceptable fit for each of the six mechanisms, thereby excluding none of the possible underlying mechanisms for heterogeneity of susceptibility to leprosy. However, the distribution of leprosy among contacts did differ between mechanisms, and predicted trends in the declining leprosy case detection were dependent on the assumed mechanism, with genetic-based susceptibility showing the slowest decline. Clustering of leprosy within households is partially caused by an increased transmission within households independent of the leprosy susceptibility mechanism. Even a large and detailed data set on contacts of leprosy patients could not unequivocally reveal the mechanism most likely responsible for heterogeneity in leprosy susceptibility.
Asunto(s)
Composición Familiar , Heterogeneidad Genética , Predisposición Genética a la Enfermedad/genética , Lepra/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Bangladesh/epidemiología , Niño , Análisis por Conglomerados , Trazado de Contacto , Femenino , Genes Dominantes/genética , Genes Recesivos/genética , Humanos , Lepra/epidemiología , Lepra/transmisión , Masculino , Persona de Mediana Edad , Modelos Genéticos , Factores de Riesgo , Adulto JovenRESUMEN
Host factors have been shown to play a significant role in the susceptibility to and clinical outcome of leprosy. Here, we analyze polymorphisms of the gene encoding ficolin-2 (FCN2), which is a soluble pattern-recognition molecule. A total of 158 patients with leprosy and 210 healthy control subjects from Brazil were investigated. Polymorphisms in the promoter and exon 8 of FCN2 were assessed by DNA sequencing. The distribution of functional FCN2 haplotypes amongpatients was significant different from that among the control subjects (P = .004). These results unveil an immunogenetic role for ficolin-2 in the host response against M. leprae.
Asunto(s)
Lectinas/genética , Lepra/genética , Mapeo Cromosómico , Cartilla de ADN , Exones , Genes Dominantes , Genes Recesivos , Haplotipos , Humanos , Lectinas/inmunología , Lepra/inmunología , Lepra/prevención & control , Polimorfismo Genético , Regiones Promotoras Genéticas , Valores de Referencia , FicolinasRESUMEN
We describe here a three year-old girl with classic clinical and histological features of juvenile hyaline fibromatosis. We found a history of similar skin findings in her eldest sister, in whom the disorder took a rapidly progressive and fatal course in the second year of life, suggesting either a very severe form of juvenile hyaline fibromatosis, or the possibility of infantile systemic hyalinosis. The similarities and differences between these two described types of hyalinoses have been reviewed in reference to the present report.
Asunto(s)
Fibromatosis Agresiva/genética , Hialina/metabolismo , Enfermedades Cutáneas Genéticas/complicaciones , Enfermedades Cutáneas Genéticas/metabolismo , Neoplasias Cutáneas/genética , Piel/metabolismo , Preescolar , Femenino , Fibromatosis Agresiva/complicaciones , Fibromatosis Agresiva/metabolismo , Fibromatosis Agresiva/fisiopatología , Genes Recesivos , Humanos , Discapacidad Intelectual/complicaciones , Enfermedades Cutáneas Genéticas/fisiopatología , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/fisiopatologíaRESUMEN
A two year-old male child presented with cutis marmorata congenita universalis, brittle hair, mild mental retardation, and finger spasms. Biochemical findings include increased levels of homocysteine in the blood-106.62 micromol/L (normal levels: 5.90-16 micromol/L). Biochemical tests such as the silver nitroprusside and nitroprusside tests were positive suggesting homocystinuria. The patient was treated with oral pyridoxine therapy for three months. The child responded well to this therapy and the muscle spasms as well as skin manifestations such as cutis marmorata subsided. The treatment is being continued; the case is reported here because of its rarity. Homocysteinuria arising due to cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder of methionine metabolism that produces increased levels of urinary homocysteine and methionine It manifests itself in vascular, central nervous system, cutaneous, and connective tissue disturbances and phenotypically resembles Marfan's syndrome. Skin manifestations include malar flush, thin hair, and cutis reticulata / marmorata.
Asunto(s)
Cistationina betasintasa/deficiencia , Homocistinuria/etiología , Administración Oral , Preescolar , Cistationina betasintasa/genética , Esquema de Medicación , Quimioterapia Combinada , Ácido Fólico/administración & dosificación , Genes Recesivos , Homocistinuria/complicaciones , Homocistinuria/tratamiento farmacológico , Humanos , Livedo Reticularis/etiología , Masculino , Errores Innatos del Metabolismo/genética , Piridoxina/administración & dosificación , Resultado del Tratamiento , Vitamina B 12/administración & dosificación , Complejo Vitamínico B/administración & dosificaciónRESUMEN
Naxos disease is a rare genodermatosis with woolly hair, keratoderma of palms and soles and cardiomyopathy. A seven-year-old boy presented with woolly hair and hyperkeratotic lesions on the palms and soles since birth. His cardiac status was evaluated and echocardiography revealed early cardiomyopathy. Scalp biopsy revealed hair shaft in an angulated outline suggestive of woolly hair. So the diagnosis of Naxos disease was made. Since he was asymptomatic no treatment was offered but a regular follow-up of the patient and treatment of emergent symptoms should prevent sudden death.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/patología , Cardiomiopatías/patología , Enfermedades del Cabello/patología , Queratodermia Palmoplantar/patología , Displasia Ventricular Derecha Arritmogénica/genética , Cardiomiopatías/genética , Niño , Genes Recesivos , Enfermedades del Cabello/genética , Humanos , Queratodermia Palmoplantar/genética , Masculino , PenetranciaRESUMEN
BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The Mitsuda reaction is a delayed granulomatous skin reaction elicited by intradermal injection of heat-killed M. leprae. Interestingly, results of the Mitsuda test are positive in the majority of individuals, even in areas not endemic for M. leprae. Like leprosy, the Mitsuda reaction is thought to be genetically controlled, but its mode of inheritance is unknown, although the role of the NRAMP1 gene has previously been reported. METHODS: We conducted a segregation analysis of quantitative Mitsuda reactivity in 168 Vietnamese nuclear families ascertained through patients with leprosy. RESULTS: We found strong evidence (P<10-9) for a major gene controlling the Mitsuda reaction independently of leprosy clinical status. Subsequent linkage analysis showed that this major gene was distinct from NRAMP1. Under the major-gene model, approximately 12% of individuals are homozygous for the recessive predisposing allele and are predicted to display high levels of Mitsuda reactivity (mean, approximately 10 mm, versus 5 mm in other individuals). CONCLUSION: We provide evidence that the Mitsuda reaction is controlled by a major gene. Our study paves the way for the identification of this gene and should provide novel insight into the mechanisms involved in granuloma formation, especially in M. leprae infection.
Asunto(s)
Predisposición Genética a la Enfermedad , Lepromina/inmunología , Lepra/epidemiología , Mycobacterium leprae/genética , Piel/inmunología , Femenino , Genes Recesivos , Haplotipos , Humanos , Inyecciones Intradérmicas , Lepra/genética , Lepra/inmunología , Lepra Lepromatosa/inmunología , Lepra Tuberculoide/epidemiología , Lepra Tuberculoide/genética , Lepra Tuberculoide/inmunología , Masculino , VietnamRESUMEN
About 75% of hereditary spherocytosis (HS) patients have the autosomal dominant form of the disease, whereas both parents of the remaining HS patients are clinically and haematologically normal. These patients could have either the autosomal recessive form of the disease or a de novo mutation. We studied 80 randomly chosen, Italian HS children with normal parents. They had different clinical phenotypes (16 mild, 40 moderate, 16 moderately severe and eight severe). These patients were screened for the occurrence of ankyrin or beta-spectrin de novo mutations. To search for ankyrin de novo mutations affecting mRNA accumulation, we studied a (AC)(n) microsatellite located in the non-coding sequence of the last exon of the ankyrin gene, and four different exonic polymorphisms in the beta-spectrin gene were utilized for the detection of de novo mutations influencing beta-spectrin mRNA stability. They were also screened for the presence of alpha-spectrin(LEPRA) as well as for the mutation -108T-->C in the ankyrin promoter, two variants previously found in some cases of genuinely recessive HS. Twenty-five patients showed ankyrin de novo mutations and 10 HS subjects had beta-spectrin de novo mutations. Furthermore, we found five patients to be heterozygous for alpha-spectrin(LEPRA) and one heterozygous for the mutation in the ankyrin promoter. Therefore, a molecular diagnosis was achieved in about 50% of the cases. Our data demonstrate that, among HS patients with normal parents, de novo dominant mutants are six times more common than recessive mutations. These results should be considered in view of the genetic counselling of a normal couple with a HS child.
Asunto(s)
Ancirinas/genética , Espectrina/genética , Esferocitosis Hereditaria/genética , Adolescente , Niño , Preescolar , Femenino , Genes Recesivos , Genotipo , Humanos , Masculino , Mutación , Linaje , Fenotipo , Regiones Promotoras GenéticasRESUMEN
We studied a recessive hereditary spherocytosis (HS) family from Norway in which all four children had haemolytic spherocytosis while spectrin (Sp) deficiency was detected in the proband. Molecular analysis demonstrated that all affected children had inherited the low expression alpha-Sp allele LEPRA (Low Expressed PRAgue) from the father. Haplotyping with a polymorphic dinucleotide repeat for the alpha-Sp gene (alphaVNTR) located in the 3' untranslated region of mRNA showed that all recessive children had inherited the same maternal alpha-spectrin allele. The paternal Sp-alphaLEPRA allele was found in cis of the polymorphic alpha-Sp Bughill allele (alphaBH) characterized by the A970D point mutation in the Sp alpha-chain. This mutation was identified on two-dimensional electrophoresis of Sp tryptic digests as an acidic shift of the alphaII tryptic domains (spots alphaIIa). Analyses of the relative expression of the paternal alpha-Sp Bughill polymorphism in the proband showed that the product of the maternal alpha-Sp gene is almost completely absent from the mature erythrocyte membrane. Comparative analysis between alphaVNTR PCR-amplified from genomic DNA and from cDNA showed that the maternal low expression alpha-Sp allele is associated with a decreased amount of mRNA. Results from molecular and biochemical studies showed that all the affected children of this family are compound heterozygous for two different low expression alpha-Sp alleles: an uncharacterized defective alpha-Sp allele on the maternal side and an alphaLEPRA allele tagged by the alphaIIa polymorphism on the paternal side.
Asunto(s)
Genes Recesivos , Espectrina/genética , Esferocitosis Hereditaria/genética , Anemia/genética , Anemia/terapia , Preescolar , Enfermedades en Gemelos/genética , Recambio Total de Sangre , Femenino , Humanos , Hiperbilirrubinemia/genética , Hiperbilirrubinemia/terapia , Lactante , Masculino , Linaje , Fototerapia , Espectrina/deficiencia , Esferocitosis Hereditaria/sangre , Gemelos Dicigóticos/genéticaRESUMEN
Data on leprosy patients have been obtained from the Dispensary of Leprosy of Campinas, São Paulo, where records on practically all cases of leprosy in the Campinas area during the period 1960-70 are filed. The whole sample comprises 10,886 individuals, distributed among 1,568 families. Complex segregation analysis was utilized to determine the nature of the genetic factors that may operate on leprosy and its subtypes. The results suggest the presence of a recessive major gene controlling susceptibility to leprosy per se, with frequency of approximately .05, although there are deviations from the expected Mendelian segregation proportions. Possible etiologic heterogeneity was examined by considering two subtypes separately: for lepromatous leprosy and tuberculoid leprosy there are suggestions for a segregating major effect; however, Mendelian transmission could not be demonstrated in either case. Therefore, there is no evidence to suggest unique genetic determinants for leprosy subtypes.
Asunto(s)
Lepra/epidemiología , Lepra/genética , Adolescente , Adulto , Brasil/epidemiología , Niño , Preescolar , Femenino , Genes Recesivos/genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Lepra/clasificación , Masculino , Meiosis , Persona de Mediana Edad , Morbilidad , Fenotipo , Prevalencia , Factores de RiesgoRESUMEN
Several lines of evidence have suggested a role of genetic factors in susceptibility to leprosy. In the mouse, natural susceptibility to infection with mycobacteria is controlled by the chromosome 1 Bcg locus, a region which is syntenic with a fragment of the human chromosome 2q, region q31-q37. It has been postulated that a human homolog of the Bcg gene controls susceptibility to leprosy per se, and may be located on chromosome 2q. In order to test the influence of this putative gene on leprosy per se, we performed linkage analyses in a set of seven multicase French Polynesian pedigrees, using an affected sib pair method and the LOD score method employing different modes of inheritance. Family members were typed for eight polymorphic loci on chromosome 2q: CRYGP1, FN, TNP1, VIL, DES, INH, PAX3, and UGT1A1. Our data provide evidence against the presence of a gene controlling susceptibility to leprosy per se on human chromosome 2q in the French Polynesian population.
Asunto(s)
Cromosomas Humanos Par 2 , Lepra/genética , Femenino , Genes Recesivos , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Escala de Lod , Masculino , Linaje , PolinesiaRESUMEN
To test the null hypothesis of random segregation of marker haplotypes from an unaffected parent to affected offspring for a one-locus autosomal recessive disease, Majumder proposed a test statistic which was shown to be locally most powerful against the alternative hypothesis of non-random segregation due to linkage between the disease and marker loci. The test procedure relied on a chi-squared approximation to the null distribution of the test statistic. In the present study, we show that the chi-squared approximation is poor for most practical situations and derive the exact null distribution of a function of the test statistic. We illustrate the method using published data on tuberculoid leprosy and HLA. We show that the test procedure is invariant, and extend the method to the case of a two-locus recessive disease.
Asunto(s)
Genes Recesivos , Tamización de Portadores Genéticos/métodos , Enfermedades Genéticas Congénitas/genética , Ligamiento Genético , Modelos Estadísticos , Distribución de Chi-Cuadrado , Femenino , Enfermedades Genéticas Congénitas/epidemiología , Haplotipos , Humanos , MasculinoRESUMEN
Sixty-three families with multiple instances of leprosy were identified through a major leprosy treatment center in northern Thailand. Complex segregation analyses for single major genes or polygenic inheritance were performed using the maximum-likelihood routine POINTER to determine the most likely etiologic model of genetic susceptibility. Liability differences between men and women were considered in these models. When individuals were considered to be affected because they had any form of leprosy, a generalized major gene model with nearly dominant parameters on the liability scale, but additive penetrances, was found to be the most likely. When only those individuals who had tuberculoid forms of leprosy were considered to be affected, a recessive model was found to be the most likely; however, the discrimination between various models was poor. Further analyses are necessary to delineate genetic mechanisms to explain these apparently divergent results. In particular, methods of testing two locus models should be considered.
Asunto(s)
Genes Recesivos , Lepra/genética , Modelos Genéticos , Adulto , Niño , Femenino , Genes Dominantes , Humanos , Masculino , Linaje , Probabilidad , Programas Informáticos , TailandiaRESUMEN
For an autosomal recessive disease, a statistical procedure is developed for detecting nonrandom segregation of marker haplotypes from an unaffected parent to affected children, specifically for the case when the alternative hypothesis of linkage between the disease and marker loci is postulated. The test procedure is locally most powerful and, depending on family size and number of families sampled, any one of the three test statistics proposed can be used. An application of this procedure provides evidence of linkage between tuberculoid leprosy and HLA.
Asunto(s)
Genes Recesivos , Enfermedades Genéticas Congénitas/genética , Ligamiento Genético , Biometría , Antígenos HLA/genética , Humanos , Lepra/genética , Lepra/inmunologíaRESUMEN
Although there is now accumulating evidence that the host response to Mycobacterium leprae is genetically controlled, the nature of the genetic component is still imprecise. Case-control studies as well as family studies, in various populations, have shown that HLA linked factors confer susceptibility to tuberculoid leprosy and lepromatous leprosy respectively. Recently, associations between Gm allotypes and the disease have also been reported. Further studies of the familial cosegregation of the different forms of leprosy together with the HLA and Gm markers may permit a better understanding of the underlying genetic mechanisms.
Asunto(s)
Antígenos HLA/genética , Lepra/genética , Complejo Mayor de Histocompatibilidad , Mapeo Cromosómico , Diagnóstico Diferencial , Susceptibilidad a Enfermedades , Genes Dominantes , Genes Recesivos , Humanos , Lepra/etnología , Lepra/inmunología , LinajeRESUMEN
Data on 72 families with multiple cases of leprosy were analyzed for a susceptibility gene linked to the HLA loci. We conducted segregation analysis with the program POINTER and identity of HLA types by descent analysis to determine the most likely mode of inheritance. We then conducted linkage analysis with the program LINKAS, first assuming linkage equilibrium and then allowing for linkage disequilibrium and etiological heterogeneity. Segregation results suggest a recessive mode of inheritance, especially for the tuberculoid forms of leprosy. The linkage results, limited to tuberculoid forms and assuming a recessive model, suggest a hypothesis of loose linkage with no unlinked locus. When an additive model is assumed, the best fit is obtained with a hypothesis of complete linkage (theta = 0.0) with heterogeneity. We currently favor the additive model as the more plausible one.
Asunto(s)
Antígenos HLA/genética , Lepra/genética , Susceptibilidad a Enfermedades , Femenino , Genes Recesivos , Ligamiento Genético , Humanos , Masculino , Modelos Genéticos , LinajeRESUMEN
Within a family, associations between a disease and a marker locus are often inferred when affected offspring share marker alleles more often than is expected by chance. Generally, this is due to nonrandom parental transmission of marker alleles and specifically could be due to linkage, epistatic gene action, or segregation distortion at the marker locus. In this paper, we discuss the statistical properties of a general test of nonrandom segregation of a marker gene. The exact probability distribution of the test under the null hypothesis of random segregation is derived, as is the distribution under the alternative hypothesis of genetic linkage. We compute the mean and variance of these distributions as a means of judging the adequacy of random segregation to explain disease-marker data but also provide a method for computing the exact significance value under the null hypothesis. These methods have been utilized for studying HLA segregation in families with tuberculoid leprosy. On the assumption that this type of leprosy is autosomal recessive, we find evidence that a gene controlling susceptibility to infection by Mycobacterium leprae resides on human chromosome 6, approximately 13 map units away from the HLA locus in males.