RESUMEN
Ototoxicity is a disabling reaction to cisplatin chemotherapy. Much of the inter-individual variability in the development of hearing impairment among cisplatin-receiving patients has not been fully accounted for. In particular, little is known about the pharmacogenomics of cisplatin-induced ototoxicity. This study sought to investigate the role of variation in five candidate genes in a cohort of South African cancer patients. Five variants within the candidate genes were genotyped in 214 patients, of which SLC22A2 rs316019 and NFE2L2 rs6721961 associated with reduced rates of ototoxicity. In the patients who were exposed to cumulative cisplatin doses ⩾200 mg m-2 (n=113), the variant rs6721961 associated with ototoxicity according to three different grading scales of hearing loss (ASHA, P=0.005; Chang, P=0.028; CTCAE, P=0.004). The NFE2L2 promotor variant rs6721961 may therefore be protective against hearing loss in cisplatin-receiving cancer patients.
Asunto(s)
Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Predisposición Genética a la Enfermedad , Pérdida Auditiva/genética , Factor 2 Relacionado con NF-E2/genética , Variantes Farmacogenómicas , Regiones Promotoras Genéticas , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Audiometría , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Pérdida Auditiva/inducido químicamente , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL), type 1 is an autosomal recessive disorder which has been identified in more than 30 affected children in the Afrikaans-speaking community of South Africa. Sequencing of B3GALT6 revealed a specific mutation, c.235A > G, in homozygous form in four families, while three others were compound heterozygotes for this mutation in combination with the c.200C > T mutation. In addition, a proband from one family carried the c.16C > T mutation combined with c.200C > T. In a series of five Iranian persons, mutations in B3GALT6 have been implicated in a syndrome characterised by skeletal abnormalities with intellectual disability, bone and connective tissue fragility. Other mutations in B3GALT6 resulted in the classical SEMD-JL phenotype in seven Japanese families and in a syndrome which has been likened to a progeroid form of Ehlers-Danlos syndrome (EDS). It is evident that there is considerable intragenic heterogeneity in B3GALT6. One of the mutations, c.200C > T, in the affected South Africans was also present in one of the Japanese persons and the respective phenotypes were identical. The multiplicity of allelic mutations and the phenotypic differences in the affected persons supports the concept that a spectrum of connective tissue disorders is programmed by mutations in B3GALT6.
Asunto(s)
Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Mutación , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Alelos , Sustitución de Aminoácidos , Niño , Análisis Mutacional de ADN , Familia , Humanos , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , SudáfricaRESUMEN
Huntington's disease (HD) correlates with abnormal expansion in a block of CAG repeats in the Huntington's disease gene. We have investigated HD evolution by typing CAG alleles in several human populations and in a variety of primates. We find that human alleles have expanded from a shorter ancestral state and exhibit unusual asymmetric length distributions. Computer simulations are used to show that the human state can be derived readily from a primate ancestor, without the need to invoke natural selection. The key element is a simple length-dependent mutational bias towards longer alleles. Our model can explain a number of empirical observations, and predicts an ever-increasing incidence of HD.
Asunto(s)
Evolución Biológica , Enfermedad de Huntington/genética , Modelos Genéticos , Mutación , Alelos , Animales , Secuencia de Bases , Simulación por Computador , Cartilla de ADN/genética , Frecuencia de los Genes , Haplotipos , Humanos , Enfermedad de Huntington/etiología , Desequilibrio de Ligamiento , Meiosis/genética , Repeticiones de Minisatélite , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos/genética , PrimatesRESUMEN
Lynch syndrome, characterized by young-onset microsatellite unstable colorectal, endometrial and other cancers, is caused by germline mutations of the mismatch repair genes, most commonly MLH1, MSH2 and MSH6. Constitutional MLH1 epimutations, which manifest as soma-wide methylation and transcriptional silencing of a single allele, have been identified in a subset of patients with a Lynch syndrome phenotype in the absence of a mismatch repair mutation. This study aimed to determine if MLH1 epimutations predispose to the development of young-onset colorectal cancer in an ethnically diverse population of South African subjects. A total of 122 index cases with a diagnosis of colorectal cancer below 50 years of age, who had tested negative for a definitive pathogenic mutation of the key mismatch repair genes, were screened for constitutional MLH1 methylation in their leukocyte DNA. Monoallelic MLH1 epimutations were identified in two sporadic cases (1.6%): a male of black African descent and an Asian Indian female. Few alleles were affected by methylation in the female, indicating mosaicism. These cases provide further evidence of the aetiological role for MLH1 epimutations in cancer development and the requirement for sensitive molecular screening techniques to identify mosaic epimutations. Furthermore, while this mechanism is rare, it affects patients of multiple ethnic origins.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas Nucleares/genética , Adulto , Metilación de ADN , Reparación de la Incompatibilidad de ADN/genética , Etnicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Mutación , SudáfricaRESUMEN
Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.
Asunto(s)
Esquizofrenia/etnología , Esquizofrenia/genética , Transmisión Sináptica/genética , Factores de Edad , Trastorno Autístico/genética , Trastorno Bipolar/genética , Dopamina/fisiología , Femenino , Variación Genética , Glutamina/fisiología , Humanos , Masculino , Mutación , Vías Nerviosas/fisiopatología , Esquizofrenia/fisiopatología , Factores Sexuales , Sudáfrica/etnología , Sinapsis/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
The 9th meeting of the African Society of Human Genetics, in partnership with the Senegalese Cancer Research and Study Group and the Human Heredity and Health in Africa (H3Africa) Consortium, was held in Dakar, Senegal. The theme was Strengthening Human Genetics Research in Africa. The 210 delegates came from 21 African countries and from France, Switzerland, UK, UAE, Canada and the USA. The goal was to highlight genetic and genomic science across the African continent with the ultimate goal of improving the health of Africans and those across the globe, and to promote the careers of young African scientists in the field. A session on the sustainability of genomic research in Africa brought to light innovative and practical approaches to supporting research in resource-limited settings and the importance of promoting genetics in academic, research funding, governmental and private sectors. This meeting led to the formation of the Senegalese Society for Human Genetics.
Le 9ème congrès de la Société Africaine de Génétique Humaine, en partenariat avec le Groupe d'Etude et de Recherche sur le Cancer (GERC) et le Consortium H3Africa, s'est tenu à Dakar, au Sénégal. Le thème était «Renforcer la recherche en Génétique Humaine en Afrique¼. Les 210 participants sont venus de 21 pays africains et de six non africains. L'objectif était de valoriser la génétique et la génomique à travers l'Afrique avec comme but ultime d'améliorer la santé des populations, et de promouvoir les carrières des jeunes chercheurs Africains. Une session sur la pérennité de la recherche génomique a révélé des approches innovantes et pratiques supportant la recherche dans des contextes de ressources limitées et l'importance de promouvoir la formation universitaire en génétique, le financement de la recherche par les gouvernements et le privé. Ce congrès conduisit à la création de la Société Sénégalaise de Génétique Humaine.
RESUMEN
Retinal degenerative disorders (RDDs) encompass a group of inherited diseases characterised by vision loss. The genetic and clinical complexity poses a challenge in unravelling the molecular genetic aetiology of this group of disorders. Furthermore, the population diversity in South Africa (SA) presents researchers with a particularly complicated task. Rapid advances in the development of cutting-edge technological platforms over the past two decades, however, have assisted in overcoming some of the challenges. The RDD research team has utilised these escalating technologies, which has facilitated a corresponding increase in molecular diagnoses. A biorepository has been established and comprises ~3 200 patient DNA samples archived with many forms of RDD (including retinitis pigmentosa, macular dystrophies, Stargardt disease, Leber congenital amaurosis, Usher syndrome and Bardet Biedl syndrome). A comprehensive review is presented of the SA journey spanning 25 years, into elucidating the molecular genetic basis of various forms of RDD in SA.
Asunto(s)
Investigación Biomédica/tendencias , Tecnología Biomédica/tendencias , Biología Molecular , Enfermedades de la Retina/fisiopatología , Humanos , Técnicas de Diagnóstico Molecular , Enfermedades de la Retina/epidemiología , Enfermedades de la Retina/genética , Sudáfrica/epidemiologíaRESUMEN
The RP17 locus for autosomal dominant retinitis pigmentosa has previously been mapped to chromosome 17q by linkage analysis. Two unrelated South African families are linked to this locus and the identification of key recombination events assigned the RP17 locus to a 10 cM interval on 17q22. The work reported here refines the mapping of the locus from a 10 cM to a 1 cM interval between the microsatellite markers D17S1604 and D17S948. A physical map of this interval was constructed using information from the Whitehead/MIT YAC contig WC 17.8. Sequence-tagged site (STS) content mapping of seven overlapping YACs from this contig was employed in order to build the map. A BAC library was screened to cover a gap in the YAC contig and two positive BACs were identified. Intragenic polymorphisms in the retinal fascin gene provided evidence for the exclusion of this candidate as the RP17 disease gene.
Asunto(s)
Proteínas Portadoras/genética , Cromosomas Humanos Par 17 , Mapeo Contig , Proteínas de Microfilamentos/genética , Retinitis Pigmentosa/genética , Cromosomas Artificiales de Levadura , Femenino , Humanos , Masculino , LinajeRESUMEN
The nucleotide sequence of the recA gene of Thiobacillus ferrooxidans has been determined. No SOS box characteristic of LexA-regulated promoters could be identified in the 196-bp region upstream from the coding region. The cloned T. ferrooxidans recA gene was expressed in Escherichia coli from both the lambda pR and lac promoters. It was not expressed from the 2.2-kb of T. ferrooxidans DNA preceding the gene. The T. ferrooxidans recA gene specifies a protein of 346 amino acids that has 66% and 69% homology to the RecA proteins of E. coli and Pseudomonas aeruginosa, respectively. Most amino acids that have been identified as being of functional importance in the E. coli RecA protein are conserved in the T. ferrooxidans RecA protein. Although some amino acids that have been associated with proteolytic activity have been substituted, the cloned protein has retained protease activity towards the lambda and E. coli LexA repressors.
Asunto(s)
Regulación de la Expresión Génica , Rec A Recombinasas/genética , Thiobacillus/genética , Secuencia de Aminoácidos , Secuencia de Bases , Western Blotting , Clonación Molecular , ADN Bacteriano/genética , Escherichia coli/genética , Datos de Secuencia Molecular , Péptido Hidrolasas , Pseudomonas aeruginosa/genéticaRESUMEN
The type II collagenopathies include a wide spectrum of phenotypes ranging from mild spondylo epiphyseal dysplasia (SED) to severe achondrogenesis/hypochondrogenesis. Several attempts have been made at providing phenotype-genotype correlations in this group of disorders. In this report we discuss a South African family in which four members have a phenotype resembling Stickler syndrome type 1. Ocular problems and conductive deafness predominate, while skeletal changes resemble those of a mild form of multiple epiphyseal dysplasia (MED). In distinction to the classical form of Stickler syndrome, the affected persons have stubby digits. DNA analysis of the exons of the COL2A1 gene documented a C-T transversion in exon 39, resulting in an Arg704Cys substitution in the triple helical domain of the type II collagen peptide; this nontermination mutation may be indicative of further heterogeneity in the Stickler group of disorders or of a new syndrome amongst the type II collagenopathies.
Asunto(s)
Anomalías Múltiples/genética , Colágeno/genética , Enfermedades del Tejido Conjuntivo/genética , Oftalmopatías/genética , Genes Dominantes , Mutación Puntual , Secuencia de Aminoácidos , Secuencia de Bases , Femenino , Ligamiento Genético , Genotipo , Humanos , Masculino , Linaje , Fenotipo , SíndromeRESUMEN
A mild autosomal dominant form of spondyloepiphyseal dysplasia (SED) is present in several generations of a South African family of English stock. This phenotype differs from that of any other previously described. Although type II collagen defects have been found in some families with SED congenita, the phenotype in our family showed discordant segregation with COL2A1 gene associated restriction fragment length polymorphisms (RFLPs), the markers for the structural locus of type II collagen. It is evident that the SED group of disorders is heterogeneous.
Asunto(s)
Colágeno/genética , Osteocondrodisplasias/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Genes Dominantes , Humanos , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Multiple epiphyseal dysplasia is broadly categorised into the more severe Fairbank and the milder Ribbing types. In this paper we document mild MED in a South African kindred, and demonstrate that heterozygosity for a mutation in the cartilage oligomeric matrix protein (COMP) gene causes the condition. The mutation, C1594G, implies a N523K substitution, altering a residue at the carboxyl-terminal end of the calmodulin-like region of COMP. The identification of this mutation demonstrates that the spectrum of manifestations from mild MED through pseudoachondroplasia can all be produced by structural mutations in COMP.
Asunto(s)
Proteínas de la Matriz Extracelular , Glicoproteínas/genética , Mutación , Osteocondrodisplasias/genética , Adulto , Proteína de la Matriz Oligomérica del Cartílago , Femenino , Ligamiento Genético , Humanos , Masculino , Proteínas Matrilinas , Persona de Mediana Edad , Osteocondrodisplasias/diagnóstico por imagen , Linaje , Polimorfismo Conformacional Retorcido-Simple , Radiografía , Análisis de Secuencia de ADN , SudáfricaRESUMEN
A genetic register for inherited retinal degenerative disorders (RDDs) has been established at the Division of Human Genetics, UCT Medical School, Cape Town, South Africa. The primary role of the register is to monitor the progress of molecular research and to facilitate the efficient delivery of services, including genetic counselling, to respective family members and new patients. The database currently holds information on 1829 subjects. The RDD-specific breakdown of the data are presented.
Asunto(s)
Sistema de Registros/estadística & datos numéricos , Degeneración Retiniana/epidemiología , Degeneración Retiniana/genética , Bases de Datos Factuales , Procesamiento Automatizado de Datos , Humanos , Sudáfrica/epidemiologíaRESUMEN
Human genomic studies have revolutionised science in high-income countries through large cohort studies (on the order of 100,000+ participants) which examine a multitude of risk factors. Yet Africa, with the most genetically diverse population in the world, large burdens of communicable and non-communicable diseases, and unique environments and risk factors, has no such large studies which comprehensively examine multiple interacting risk factors for disease. We argue that establishing such studies is overdue. Scientific discoveries from large cohort studies can drive innovation, foster training and local capacity building, and provide vital evidence for public health decision making. Furthermore, evidence from studies in Africa could provide insights to disease processes relevant to other populations around the globe. The enormous potential for genetic and epidemiologic discovery in Africa should not continue to go untapped. Combining powerful genomic tools with epidemiology through large cohort studies could dramatically advance public health in Africa.
Asunto(s)
Genómica , Epidemiología Molecular , Salud Pública/métodos , África , Humanos , Innovación Organizacional , Estudios ProspectivosRESUMEN
Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Predisposición Genética a la Enfermedad , Heterocigoto , Neoplasias/epidemiología , Neoplasias/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Edad , Índice de Masa Corporal , Lactancia Materna , Femenino , Humanos , Menarquia , Menopausia , Homólogo 1 de la Proteína MutL , Mutación , Proteínas Nucleares/genética , Paridad , Linaje , Embarazo , Factores de Riesgo , HermanosAsunto(s)
Degeneración Retiniana/epidemiología , Degeneración Retiniana/genética , Proteínas Portadoras/genética , Mapeo Cromosómico , Cromosomas Humanos Par 17/genética , Estudios de Cohortes , Genes Dominantes , Genes Recesivos , Ligamiento Genético , Pruebas Genéticas , Humanos , Biología Molecular/métodos , Mutación , Prevalencia , Proteínas de Unión al ARN , Retinitis Pigmentosa/genética , Rodopsina/genética , Sudáfrica/epidemiologíaAsunto(s)
Transportadoras de Casetes de Unión a ATP/genética , ADN/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Mutación , Enfermedades de la Retina , Humanos , Incidencia , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/epidemiología , Enfermedades de la Retina/genética , Sudáfrica/epidemiologíaRESUMEN
BACKGROUND: It is difficult to provide a colonoscopic surveillance service for at-risk family members with hereditary nonpolyposis colorectal carcinoma when many of those family members live in a remote area of South African far from endoscopic services. A mobile surveillance programme was established to service these individuals. OBJECTIVE: The aim of this study was to compare the quality of the mobile service to that provided in established endoscopy units. METHOD: Ninety-one asymptomatic subjects with known disease-causing mutations underwent 259 colonoscopies. Of these, 171 colonoscopies were performed by a mobile colonoscopy service in small rural hospitals and 88 in established endoscopy units. The quality of the colonoscopic services was measured by completion rate, the rate of detection of colonoscopic abnormalities, histopathological analyses of biopsies, surgical intervention and colorectal cancer deaths. RESULTS: The caecum was reached in 96% of all colonoscopies. A significant lesion was detected in 8.8% of colonoscopies. There was no difference in the rate of complete colonoscopy and detection rate of lesions in the established units and the mobile service (both P = 0.6). The rate of detection of early adenocarcinomas was similar (P = 0.17). The colonoscopic screening/surveillance programme meets international standards with a high accuracy (95.75%) and negative predictive value (100%). CONCLUSION: The mobile service provides access to colonoscopy in remote areas without compromising the quality of service.
Asunto(s)
Colonoscopía/métodos , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Unidades Móviles de Salud/normas , Vigilancia de la Población/métodos , Calidad de la Atención de Salud , Colonoscopía/normas , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Humanos , Servicios de Salud Rural/normas , Sudáfrica/epidemiologíaRESUMEN
A recombinant plasmid, pRSR100, containing the functional analogue of the Escherichia coli recA gene was isolated from a genomic library of Thiobacillus ferrooxidans ATCC 33020. The plasmid complemented defects in DNA repair and homologous recombination in E. coli recA mutant strains. Antiserum raised against E. coli RecA protein reacted with the native but defective E. coli HB101 RecA protein; it did not react with protein extracts from the recA deletion mutant E. coli JK696, but it reacted with two protein bands in extracts of E. coli JK696(pRSR100). A single band with an apparent Mr equal to the higher-Mr band in E. coli JK696(pRSR100) was detected in T. ferrooxidans cell extracts with the E. coli RecA antiserum.