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INTRODUCTION: Neurodevelopmental disorders (NDDs) are diverse and can be explained by either genomic aberrations or single nucleotide variants. Most likely due to methodological approaches and/or disadvantages, the concurrence of both genetic events in a single patient has hardly been reported and even more rarely the pathogenic variant has been regarded as the cause of the phenotype when a chromosomal alteration is initially identified. CASE PRESENTATION: Here, we describe a NDD patient with a 6p nonpathogenic paracentric inversion paternally transmitted and a de novo pathogenic variant in the GRIN2B gene. Molecular-cytogenetic studies characterized the familial 6p inversion and revealed a paternal 9q inversion not transmitted to the patient. Subsequent whole-genome sequencing in the patient-father dyad corroborated the previous findings, discarded inversions-related cryptic genomic rearrangements as causative of the patient's phenotype, and unveiled a novel heterozygous GRIN2B variant (p.(Ser570Pro)) only in the proband. In addition, Sanger sequencing ruled out such a variant in her mother and thereby confirmed its de novo origin. Due to predicted disturbances in the local secondary structure, this variant may alter the ion channel function of the M1 transmembrane domain. Other pathogenic variants in GRIN2B have been related to the autosomal dominant neurodevelopmental disorder MRD6 (intellectual developmental disorder, autosomal dominant 6, with or without seizures), which presents with a high variability ranging from mild intellectual disability (ID) without seizures to a more severe encephalopathy. In comparison, our patient's clinical manifestations include, among others, mild ID and brain anomalies previously documented in subjects with MRD6. CONCLUSION: Occasionally, gross chromosomal abnormalities can be coincidental findings rather than a prime cause of a clinical phenotype (even though they appear to be the causal agent). In brief, this case underscores the importance of comprehensive genomic analysis in unraveling the wide-ranging genetic causes of NDDs and may bring new insights into the MRD6 variability.
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Inversão Cromossômica , Transtornos do Neurodesenvolvimento , Receptores de N-Metil-D-Aspartato , Feminino , Humanos , Masculino , Cromossomos Humanos Par 6/genética , Transtornos do Neurodesenvolvimento/genética , Linhagem , Fenótipo , Receptores de N-Metil-D-Aspartato/genética , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Colorectal cancer (CRC) ranks third in cancer incidence globally and is the second leading cause of cancer-related mortality. The nucleoside diphosphate kinase 1 (NME1) and netrin 1 receptor (DCC) genes have been associated with resistance against tumorigenesis and tumor metastasis. This study investigates the potential association between NME1 (rs34214448 G > T and rs2302254 C > T) and DCC (rs2229080 G > C and rs714 A > G) variants and susceptibility to colorectal cancer development. METHODS: Samples from 232 colorectal cancer patients and 232 healthy blood donors underwent analysis. Variants were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Associations were assessed using odds ratios (OR), and the p values were adjusted with Bonferroni test. RESULTS: Individuals carrying the G/T and T/T genotypes for the NME1 rs34214448 variant exhibited a higher susceptibility for develop colorectal cancer (OR = 2.68, 95% CI: 1.76-4.09, P = 0.001 and OR = 2.47, 95% CI: 1.37-4.47, P = 0.001, respectively). These genotypes showed significant associations in patients over 50 years (OR = 2.87, 95% CI: 1.81-4.54, P = 0.001 and OR = 2.99, 95% CI: 1.54-5.79, P = 0.001 respectively) and with early Tumor-Nodule-Metastasis (TNM) stage (P = 0.001), and tumor location in the rectum (P = 0.001). Furthermore, the DCC rs2229080 variant revealed that carriers of the G/C genotype had an increased risk for develop colorectal cancer (OR = 2.00, 95% CI: 1.28-3.11, P = 0.002) and were associated with age over 50 years, sex, and advanced TNM stages (P = 0.001). CONCLUSIONS: These findings suggest that the NME1 rs34214448 and DCC rs2229080 variants play a significant role in colorectal cancer development.
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Neoplasias Colorretais , Neoplasias Gástricas , Humanos , Pessoa de Meia-Idade , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Genótipo , Neoplasias Gástricas/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Estudos de Casos e Controles , Receptor DCC/genética , Nucleosídeo NM23 Difosfato Quinases/genéticaRESUMO
BACKGROUND: miRNAs are non-coding RNAs participating actively in the post-translational regulation of oncogenes, tumor suppressor, and DNA repair genes implicated in colorectal cancer (CRC). This study aims to examine the association of the variants miR-27a (rs895819 A>G), miR-196a2 (rs11614913 T>G) and miR-146a (rs2910164 C>G) in Mexican CRC patients. METHODS: DNA samples from 183 patients and 186 healthy Mexican subjects were analyzed. Variants were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) and adjusted by the Bonferroni test. RESULTS: Patients carrying the G/G genotype of the rs895819 variant in the miR-27a gene showed an increased risk of CRC (19% vs 12%, P=0.013). A similar tendency was noticed for patients younger than 50 years carrying A/G (48% vs 41%, P=0.014). The A/G genotype in TNM stages I+II (55.7% vs 40.8%, P=0.011) and tumor location in the colon (69.5 vs 40.8%, P=0.001) were also increased. For the variant rs11614913 of the miR-196a2 gene, carriers of the C/C genotype showed an increased risk of CRC (32% vs 22%, P=0.009). This genotype was more frequent in TNM stage III+IV (36.8% vs 22.5%, P=0.007) and the tumor had a more recurrent location in the rectum (31.6% vs 22.5%, P=0.013). The rs2910164 variant of the miR-146a gene was found to have no significant risk associations. CONCLUSION: Our results reveal that the rs895819 variant in miR-27a and rs11614913 in miR-196a2 have a substantial impact on the development of CRC.
Assuntos
Neoplasias Colorretais , MicroRNAs , Humanos , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Genótipo , MicroRNAs/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Colorectal cancer (CRC) is the third most common cancer in the world. Overall survival is related to clinical stage: more advanced stages show lower survival rates; therefore, they need to be monitored regularly with new, less invasive and more specific biomarkers. The concentration and integrity index of circulating cell-free DNA (ccfDNA) have been proposed as potential diagnostic and prognostic biomarkers for CRC, however, inconsistent results are still observed in different reports. Here we analyze these potential CRC biomarkers in a Mexican population. In this study, 124 patients with sporadic CRC and 37 healthy individuals were examined as a reference group. The ccfDNA was isolated from plasma samples of all included subjects. The ccfDNA concentration was determined by fluorometry and the integrity index (ALU247/ALU115 ratio) by quantitative PCR amplification (qPCR) of ALU sequences. The results show that ccfDNA concentration was higher in CRC patients than in the reference group (P=0.001). The integrity index showed no significant differences between these groups (P=0.258), except for histological type (P=0.012). A higher ccfDNA concentration was also associated with patients younger than 50 years (P=0.030). The ccfDNA concentration showed significant discriminatory power (AUC: 0.854, C.I.: 0.78-0.92, P=0.001) between patients and the reference group and between tumor-node-metastasis (TNM) stages. In conclusion, ccfDNA concentration proves to be a good diagnostic biomarker for CRC patients, whereas the integrity index did not show diagnostic utility.
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Ácidos Nucleicos Livres , Neoplasias Colorretais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA , Humanos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death worldwide. Down-regulation of the cysteine-rich reversion-inducing protein with Kazal motifs (RECK) has been confirmed in numerous human cancers and is clinically associated with metastasis. This study aims to explore, for the first time, the possible association of the RECK variants rs11788747 and rs10972727 with CRC susceptibility and clinicopathological features. DNA from 130 CRC patients and 130 healthy blood donors was analyzed. Identification of genetic variants was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated using the odds ratio (OR) test and P values were adjusted using the Bonferroni test. Individuals carrying the G/G genotype for the rs11788747 variant showed a lower risk of colorectal cancer (OR 0.33; 95% CI 0.16-0.70; P = 0.006). Patients older than 50 years who carry the G/G genotype have a lower risk of CRC (OR 0.26; 95% CI 0.09-0.73; P = 0.019) and of developing advanced tumor-nodule-metastasis (TNM) stages (OR 0.23; 95% CI 0.09-0.54; P = 0.001). Individuals carrying the A/A genotype of the rs10972727 variant also showed decreased risk of CRC (OR 0.38; 95% CI 0.19-0.77; P = 0.011), and were associated with age (over 50 years), sex, advanced TNM stages, and tumor location in the colon. Our results suggest that the RECK variants studied here (rs11788747 and rs10972727) are associated with decreased CRC risk, TNM stages and tumor location.
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Neoplasias Colorretais , Predisposição Genética para Doença , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas Ligadas por GPI/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
This study intends to describe for the first time a cohort of Mexican patients with Costello syndrome. The five exons of the HRAS gene were amplified in DNA samples from 13 patients with a clinical suspicion of Costello syndrome. PCR products were sequenced using the Ready Reaction Big Dye Terminator v.3.0 Kit and an ABI PRISM 310 sequencer. Only five patients (38%) showed causal variant in codon 12 of the HRAS gene (four with the p.Gly12Ser and one with the p.Gly12Ala variant). Three patients showed silent polymorphic variants (p.His27His and p.Leu159Leu). Clinical features in patients carrying the causal variant were variable. The alternative diagnosis of cardio-facio-cutaneous syndrome was considered in patients who did not have a causative variant in HRAS.
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Síndrome de Costello , Displasia Ectodérmica , Proteínas Proto-Oncogênicas p21(ras) , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Fácies , Insuficiência de Crescimento , Humanos , México , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: Mutations and polymorphisms of the GSK3ß gene have been associated with several diseases including Alzheimer disease, diabetes and cancer; however, to date, no variants of this gene have been associated with colorectal cancer (CRC). This study aims to explore, for the first time, the association of the GSK3ß rs334558 and rs6438552 polymorphisms with CRC. METHODS: Genomic DNA from 330 CRC patients and healthy blood donors were analyzed. Identification of polymorphisms was made by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test. RESULTS: Patients carrying the C/T genotype for the rs334558 (T>C) polymorphism showed an increased risk for CRC (OR = 1.71, 95% CI: 1.05-2.79, P = 0.039); this association was also observed for TNM stage and tumor location. For the rs6438552 (T>C) polymorphism, the OR analysis showed that patients carrying C/T and C/C genotypes have a decreased risk for CRC (OR = 0.44, 95% CI: 0.27-0.70, P = 0.001 and OR = 0.24, 95% CI: 0.10-0.64, P = 0.001, respectively); this decreased risk was also evident in the stratified analysis by TNM stage and tumor location. Haplotype analysis of these 2 loci of GSK3ß (rs334558 and rs6438552) showed differential distribution. The T-T and C-C haplotype was associated with a decreased risk of CRC, while the T-C haplotype was associated with an increased risk of CRC. CONCLUSION: Our results denote that GSK3ß gene polymorphisms play a significant role in promoting or preventing CRC. Additionally, variations in this gene are associated with the tumor site and the tumor-node-metastasis (TNM) stage in these patients.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Glicogênio Sintase Quinase 3 beta/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Williams-Beuren syndrome (WBS) has a prevalence of 1/7500-20000 live births and results principally from a de novo deletion in 7q11.23 with a length of 1.5 Mb or 1.8 Mb. This study aimed to determine the frequency of 7q11.23 deletion, size of the segment lost, and involved genes in 47 patients with a clinical diagnosis of WBS and analysed by fluorescence in situ hybridization (FISH); among them, 31 had the expected deletion. Micro-array comparative genomic hybridization (aCGH) confirmed the loss in all 18 positive-patients tested: 14 patients had a 1.5 Mb deletion with the same breakpoints at 7q11.23 (hg19: 72726578-74139390) and comprising 24 coding genes from TRIM50 to GTF2I. Four patients showed an atypical deletion: two had a 1.6 Mb loss encompassing 27 coding genes, from NSUN5 to GTF2IRD2; another had a 1.7 Mb deletion involving 27 coding genes, from POM121 to GTF2I; the remaining patient presented a deletion of 1.2 Mb that included 21 coding genes from POM121 to LIMK1. aCGH confirmed the lack of deletion in 5/16 negative-patients by FISH. All 47 patients had the characteristic facial phenotype of WBS and 45 of 47 had the typical behavioural and developmental abnormalities. Our observations further confirm that patients with a classical deletion present a typical WBS phenotype, whereas those with a high (criteria of the American Association of Pediatrics, APP) clinical score but lacking the expected deletion may harbour an ELN point mutation. Overall, the concomitant CNVs appeared to be incidental findings.
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Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Hibridização Genômica Comparativa/métodos , Hibridização in Situ Fluorescente/métodos , Síndrome de Williams/genética , Adolescente , Criança , Pré-Escolar , Bandeamento Cromossômico , Feminino , Humanos , Lactente , Cariotipagem , Masculino , México , Síndrome de Williams/diagnósticoRESUMO
PURPOSE: Several studies have shown a strong association between diabetes mellitus (DM) and increased risk of colorectal cancer (CRC). The fundamental mechanisms that support this association are not entirely understood; however, it is believed that hyperinsulinemia and hyperglycemia may be involved. Some proposed mechanisms include upregulation of mitogenic signaling pathways like MAPK, PI3K, mTOR, and WNT, which are involved in cell proliferation, growth, and cancer cell survival. The purpose of this study was to evaluate the gene expression profile and identify differently expressed genes involved in mitogenic pathways in CRC patients with and without DM. METHODS: In this study, microarray analysis of gene expression followed by quantitative PCR (qPCR) was performed in cancer tissue from CRC patients with and without DM to identify the gene expression profiles and validate the differently expressed genes. RESULTS: Among the study groups, some differently expressed genes were identified. However, when bioinformatics clustering tools were used, a significant modulation of genes involved in the WNT pathway was evident. Therefore, we focused on genes participating in this pathway, such as WNT3A, LRP6, TCF7L2, and FRA-1. Validation of the expression levels of those genes by qPCR showed that CRC patients without type 2 diabetes mellitus (T2DM) expressed significantly more WNT3Ay LRP6, but less TCF7L2 and FRA-1 compared to controls, while in CRC patients with DM the expression levels of WNT3A, LRP6, TCF7L2, and FRA-1 were significantly higher compared to controls. CONCLUSIONS: Our results suggest that WNT/ß-catenin pathway is upregulated in patients with CRC and DM, demonstrating its importance and involvement in both pathologies.
Assuntos
Neoplasias Colorretais/genética , Diabetes Mellitus Tipo 2/genética , Via de Sinalização Wnt/fisiologia , beta Catenina/genética , Idoso , Neoplasias Colorretais/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , México , Pessoa de Meia-IdadeRESUMO
To estimate the frequency of monoclonal B cells in Mexican general population from two different regions of Mexico. Monoclonal B cells were detected by rearrangements of the immunoglobulin heavy chains (IGH) in 288 individuals: 188 from a metropolitan area and 100 from a rural area. After DNA extraction from peripheral blood by the CTAB/DTAB method, multiplex PCR was used to amplify the IGH rearrangements, followed by capillary electrophoresis. In together, 9.4% of the studied individuals showed monoclonal B cells. This prevalence is significantly higher to those previously described for other populations, but similar to a report in the Spanish population. Among people from the metropolitan area, 12.8% exhibited monoclonal B cells in comparison with 3% of people from the rural area. All individuals showing monoclonal B cells were elder than 40 years. Higher frequency of incomplete monoclonal rearrangements was observed. Individuals from urban areas show significantly increased frequencies of monoclonal B cells regarding the people from the rural area. It is reasonable to believe that the environmental factor could have a greater impact on the development of monoclonality than the genetic component.
Assuntos
Linfócitos B/metabolismo , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Células Clonais , Feminino , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , México , Pessoa de Meia-Idade , População Rural , População Urbana , Adulto JovemRESUMO
AIM: The aim of this study was to investigate the association of the rs2240308 and rs1133683 polymorphisms in the AXIN2 gene with colorectal cancer (CRC) in Mexican patients. MATERIALS AND METHODS: Genomic DNAs from 201 CRC patients and 100 healthy blood donors were analyzed for AXIN2 gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Statistical associations were calculated using the odds ratio (OR) test. RESULTS: The genotype distribution of the rs1133683 polymorphism C > T showed a statistical difference between the two study groups (p = 0.0019). Moreover, OR analyses demonstrated that individuals with either the C/T or T/T genotype have a decreased risk for CRC compared with individuals with the C/C genotype (OR = 0.47, 95% confidence interval [CI] = 0.25-0.86, p = 0.0134 and OR = 0.24, 95% CI = 0.10-0.57, p = 0.005, respectively). This association was also evident in a stratified analysis based on tumor-node-metastasis (TNM) stage. For the rs2240308 polymorphism C > T, the OR analysis showed a significantly increased risk for carriers of the T/T genotype (OR = 2.64, 95% CI = 1.12-6.24, p = 0.0236) and this association was also evident in the stratified analysis by TNM stage. CONCLUSION: Our results indicate the possibility that variations in the AXIN2 gene may play a significant role in promoting or preventing CRC development.
Assuntos
Proteína Axina/genética , Neoplasias Colorretais/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Alelos , Proteína Axina/metabolismo , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
Multiple myeloma (MM) is characterized by abnormal proliferation of clonal plasma cells or monoclonal plasmacytosis, resulting in accumulation of clonal immunoglobulins. Monoclonal gammopathy of unknown significance (MGUS) is considered a premorbid stage for developing MM. Studies have shown an increased risk of MGUS in first-degree relatives of patients with MM. Detection of immunoglobulin heavy chain gene (IGH) rearrangement provides a useful tool for assessing clonality. The aim of this study was to determine clonality in peripheral blood samples from 61 healthy first-degree relatives of MM probands by sorting circulating lymphocytes and detection of the IGH rearrangements in these cells. We detected 16 out of 61 (26.2%) relatives with monoclonal complete and incomplete IGH rearrangements; only three of them showed elevated monoclonal immunoglobulin in the serum protein electrophoresis. We conclude that this strategy is able to identify efficiently clonality in peripheral blood samples from first-degree relatives of patients with MM, who have a non-negligible risk of developing MGUS or other plasma cell dyscrasias.
Assuntos
Rearranjo Gênico , Cadeias Pesadas de Imunoglobulinas/sangue , Mieloma Múltiplo/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Adolescente , Adulto , Idoso de 80 Anos ou mais , Proliferação de Células , Separação Celular , Eletroforese Capilar , Saúde da Família , Feminino , Citometria de Fluxo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Células Neoplásicas Circulantes , Plasmócitos/citologiaRESUMO
Ataxia telangiectasia (AT) is a chromosomal instability syndrome with autosomal recessive inheritance, it is caused by more than 500 mutations of the ATM gene, which is involved in the cellular response to DNA damage. The diagnosis becomes difficult due to the evolution of the disease, their poor knowledge, and limited access to diagnostic tests. Chromosomal damage induced by ionizing radiation (IR) assay is still a sensitive method for early diagnosis, and it is essential for better management and genetic counseling. This paper shows diagnosis and follow-up in four cases with AT.
Assuntos
Ataxia Telangiectasia/diagnóstico , Adolescente , Criança , Feminino , Seguimentos , Humanos , MasculinoRESUMO
Xq28 duplication, including the MECP2 gene, is among the most frequently identified Xq subtelomeric rearrangements. The resulting clinical phenotype is named Lubs syndrome and mainly consists of intellectual disability, congenital hypotonia, absent speech, recurrent infections, and seizures. Here we report a Mexican male patient carrying a supernumerary marker chromosome with de novo Xq28 gain. By MLPA, duplication of MECP2, GDI1, and SLC6A8 was found and a subsequent a-CGH analysis demonstrated that the gain spanned ~2.1Mb. Despite gain of the MECP2 gene, the features of this patient do not evoke Lubs syndrome. Probably the mosaicism of the supernumerary marker chromosome is modifying the phenotype in this patient.
Assuntos
Síndrome de Resistência a Andrógenos/genética , Duplicação Cromossômica/genética , Anormalidades Craniofaciais/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Proteína 2 de Ligação a Metil-CpG/genética , Transtornos dos Cromossomos Sexuais/genética , Adolescente , Síndrome de Resistência a Andrógenos/patologia , Fácies , Proteína do X Frágil da Deficiência Intelectual/genética , Marcadores Genéticos , Variação Genética , Humanos , Lactente , Masculino , México , Reação em Cadeia da Polimerase Multiplex , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genéticaRESUMO
INTRODUCTION: Beckwith-Wiedemann syndrome is an overgrowth syndrome that is characterized by hypoglycemia at birth, coarse face, hemihypertrophy and an increased risk to develop embryonal tumors. In approximately 15% of patients, the inheritance is autosomal dominant with variable expressivity and incomplete penetrance, whereas the remainder of Beckwith-Wiedemann syndrome cases are sporadic. Beckwith-Wiedemann syndrome molecular etiologies are complex and involve the two imprinting centers 1 (IC1) and 2 (IC2) of 11p15 region. This case report describes, for the first time, the unusual association of ovotesticular disorder in a patient from Morelia, Mexico with Wiedemann-Beckwith syndrome. CASE PRESENTATION: We report the case of a Mexican six-year-old girl with Beckwith-Wiedemann Syndrome, ambiguous genitalia, and bilateral ovotestes. She has a 46,XX karyotype without evidence of Y-chromosome sequences detected by fluorescence in situ hybridization with both SRY and wcp-Y probes. CONCLUSION: Although a random association between these two conditions cannot be excluded, future analysis of this patient with Beckwith-Wiedemann syndrome and 46,XX ovotesticular disorder may lead to new insights into these complex pathologies. We speculate that a possible misregulation in the imprinted genes network has a fundamental role in the coexistence of these two disorders.
RESUMO
Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger. An "angel-shaped phalanx" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias, such as angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. BDC and ASPED result from mutations in the CDMP1 gene. We report here a Mexican patient with BDC and clinical features of ASPED who carries a novel mutation in CDMP1, confirming that BDC and ASPED are part of the CDMP1 mutational spectrum. Based on the large number of clinical features in common, we suggest that both anomalies are part of the same clinical spectrum. Supported by an extensive review of the literature, a possible genotype-phenotype correlation in the mutational spectrum of this gene is proposed.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Braquidactilia/genética , Fator 5 de Diferenciação de Crescimento/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Braquidactilia/diagnóstico , Braquidactilia/diagnóstico por imagem , Criança , Epífises/diagnóstico por imagem , Dedos/anormalidades , Mutação da Fase de Leitura , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Radiografia , Deleção de SequênciaRESUMO
BACKGROUND: WNT7a, a member of the Wnt ligand family implicated in several developmental processes, has also been reported to be dysregulated in some types of tumors; however, its function and implication in oncogenesis is poorly understood. Moreover, the expression of this gene and the role that it plays in the biology of blood cells remains unclear. In addition to determining the expression of the WNT7A gene in blood cells, in leukemia-derived cell lines, and in samples of patients with leukemia, the aim of this study was to seek the effect of this gene in proliferation. METHODS: We analyzed peripheral blood mononuclear cells, sorted CD3 and CD19 cells, four leukemia-derived cell lines, and blood samples from 14 patients with Acute lymphoblastic leukemia (ALL), and 19 clinically healthy subjects. Reverse transcription followed by quantitative Real-time Polymerase chain reaction (qRT-PCR) analysis were performed to determine relative WNT7A expression. Restoration of WNT7a was done employing a lentiviral system and by using a recombinant human protein. Cell proliferation was measured by addition of WST-1 to cell cultures. RESULTS: WNT7a is mainly produced by CD3 T-lymphocytes, its expression decreases upon activation, and it is severely reduced in leukemia-derived cell lines, as well as in the blood samples of patients with ALL when compared with healthy controls (p ≤0.001). By restoring WNT7A expression in leukemia-derived cells, we were able to demonstrate that WNT7a inhibits cell growth. A similar effect was observed when a recombinant human WNT7a protein was used. Interestingly, restoration of WNT7A expression in Jurkat cells did not activate the canonical Wnt/ß-catenin pathway. CONCLUSIONS: To our knowledge, this is the first report evidencing quantitatively decreased WNT7A levels in leukemia-derived cells and that WNT7A restoration in T-lymphocytes inhibits cell proliferation. In addition, our results also support the possible function of WNT7A as a tumor suppressor gene as well as a therapeutic tool.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfócitos T/metabolismo , Proteínas Wnt/metabolismo , Adulto , Idoso , Análise de Variância , Antígenos CD19/imunologia , Western Blotting , Complexo CD3/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Humanos , Células Jurkat/efeitos dos fármacos , Células Jurkat/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Proteínas Recombinantes/farmacologia , Linfócitos T/imunologia , Proteínas Wnt/genética , Proteínas Wnt/farmacologiaRESUMO
The Wnt-ß-catenin signalling pathway plays a crucial role in the regulation, differentiation, proliferation and cellular death processes; consequently, alterations in this pathway are involved in numerous abnormalities of development, growth and homeostasis in animal organisms. Wnt proteins include a numerous family of secretion glycoproteins which join to Frizzled receptors and Low Density Lipoprotein Receptor-related Protein, in order to stabilize the critical ß-catenin protein, and to initiate an intricate signaling cascade, which is related to multiple nucleocytoplasmatic processes. Alterations in the canonical Wnt-ß-catenin signaling pathway have been associated with variations in a number of proteins participating in this route, or with activation / inactivation of oncogenes and tumor suppressor genes, which explain different processes of tumorigenesis, in addition to a number of malformations and human diseases. This review describes the relations between the Wnt-ß-catenin signaling pathway with different neoplasic processes, as well as its application in the diagnosis and prognosis of cancer.
Assuntos
Neoplasias/fisiopatologia , Via de Sinalização Wnt , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Terapia Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Leucemia/genética , Leucemia/metabolismo , Leucemia/fisiopatologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/fisiologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Proteínas Wnt/fisiologia , beta Catenina/fisiologiaRESUMO
Molecular diagnosis of fragile X syndrome (FXS) is carried out by Southern blot or polymerase chain reaction-Southern analysis; however, these procedures are expensive and time consuming, making it impractical for mass screening programs. Willemsen et al. developed and tested the diagnostic potential of a rapid antibody test on blood smears, based on the presence of fragile X mental retardation protein (FMRP) in peripheral lymphocytes from normal individuals and its absence in male patients with FXS. The diagnostic power of this antibody test is perfect for men, whereas the results are less specific for women. Validation of this procedure has been achieved mainly in the Caucasian population, but no reports including Latin American individuals have been published. To test this procedure, expression of FMRP in peripheral lymphocytes was achieved both in Mexican FXS patients and normal men and was compared with the molecular analysis of the CGG repetitive sequences of the FMR1 gene. The results of the antibody test, which measure the FMRP expression, entirely correlated with the molecular tests using polymerase chain reaction on DNA modified. Sensitivity and specificity of the test and the positive and negative predictive values were 100%. This noninvasive test requires one or two blood drops; it is rapid, simple, and inexpensive, making this procedure an ideal choice for screening large groups of male patients with mental retardation.
Assuntos
Coleta de Amostras Sanguíneas , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/sangue , Síndrome do Cromossomo X Frágil/diagnóstico , Coleta de Amostras Sanguíneas/métodos , Estudos de Casos e Controles , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Expressão Gênica , Genética Populacional , Humanos , Imuno-Histoquímica/métodos , Masculino , México , Técnicas de Diagnóstico Molecular/métodos , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
Huntington's disease (HD) is a neurological degenerative disorder, inherited by an autosomal dominant mode, and caused by a CAG triplet expansion coding for a poly-glutamine sequence in the huntingtin protein. HD affects 5-10 in 100,000 individuals from Caucasian population. Clinically patients display motor, cognitive and psychological impairment, and death within 10-15 years. Concrete advances have been achieved in the knowledge of the mutational mechanism, alteration of the protein product and their neuropathological effects. A number of tests such as PCR with or without DNA modification, Southern blot and mixed methods are analyzed. We describe their characteristics and effectiveness for the molecular diagnosis of HD.