RESUMO
INTRODUCTION: There is a scarcity of data on height as well as bone densitometry in humans with NOGGIN mutations. METHODS: In 2 families with symphalangism, anthropometry, bone densitometry and genetic analysis of the NOGGIN gene were performed. RESULTS: In family A, the height standard deviation scores of the affected father and son were -0.4 and 3.5, respectively. In family B, the height standard deviation scores of the affected father, twin daughters and another daughter were 1.7, 1.8, 2.4 and 1.8, respectively. In the children, percentage predicted bone mineral content (BMC) for height at the appendicular sites (total femur, femoral neck) was lower than at an axial site lumbar spine. In the 2 fathers, median bone mineral density at total femur and femoral neck was -0.3 standard deviation scores (-0.7, 0.2) and at lumbar spine the scores were -0.4 and 0.9. The children had median tibial and radial speed of sound velocities of -2.1 (-0.9 to -6.4) and -1.4 (-0.2 to -4.9), respectively. DNA analysis revealed a novel missense mutation in family A and family B, resulting in a Met190Val substitution and a Pro42Arg substitution, respectively. CONCLUSION: Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults. The appendicular BMC and speed of sound may be low in affected children but normalises by adulthood. However, axial BMC seems normal in childhood and is high in adulthood.
Assuntos
Estatura/genética , Desenvolvimento Ósseo/genética , Proteínas de Transporte/genética , Mutação de Sentido Incorreto/genética , Adolescente , Adulto , Densidade Óssea/genética , Criança , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Sinostose/genéticaRESUMO
AIMS: To explore the role of the Peutz-Jeghers gene (LKB1) in sporadic breast and colon cancers. METHODS: Thirty consecutive sporadic carcinomas of the breast and 23 of the colon were selected. DNA was extracted from paraffin wax embedded tissue and analysed for loss of heterozygosity (LOH) at microsatellite markers D19S886 and D19S565 close to the LKB1 gene. Tumours showing LOH were screened for LKB1 mutations by single strand conformational polymorphism (SSCP). RESULTS: Five breast carcinomas showed LOH (21% and 7% of those informative for D19S886 and D19S565, respectively). Five of the colorectal carcinomas showed LOH (15% and 36% of those informative for D19S886 and D19S565, respectively), with one sample showing allele loss with both markers. Screening of these 10 carcinomas by SSCP identified one migrational shift but sequencing revealed an intronic polymorphism only. Therefore, no coding mutations were found in these carcinomas. CONCLUSIONS: These findings suggest that although allele loss at the LKB1 locus occurs relatively frequently in sporadic breast and colon cancers, mutations do not seem to be a feature.
Assuntos
Neoplasias da Mama/genética , Neoplasias do Colo/genética , Proteínas de Neoplasias/genética , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases/genética , Quinases Proteína-Quinases Ativadas por AMP , Feminino , Marcadores Genéticos , Humanos , Perda de Heterozigosidade , MutaçãoRESUMO
Epigenetic mechanisms in carcinogenesis may have a significant role in the development of colorectal cancer. To investigate this phenomenon in early-stage disease, promoter methylation status in the tumour suppressor genes APC, MGMT, hMLH1, P14/P14ARF, and CDKN2A/P16 was investigated in 78 colorectal adenomas. These had previously been characterized for mutations of APC, KRAS, and TP53 genes and for chromosomal abnormality by comparative genomic hybridization (CGH). APC hypermethylation was seen in 52 tumours (66.7%). APC showed either methylation or mutation in 66 lesions (84.6%), but these events were not statistically associated. MGMT methylation was detected in 39 cases (50%). Adenomas with this abnormality showed a significantly lower number of chromosomal changes by CGH (p < 0.02), confirming that DNA repair defect of this type is associated with a lower level of chromosomal instability. An hMLH1 methylation defect was seen in only one adenoma (1.3%), from a patient who had a synchronous cancer showing the same defect. Methylation of P14 (P14ARF) was seen in 31 adenomas (39.7%) and CDKN2A (P16) abnormality in 25 (32.1%). DNA methylation at two or more loci was seen in 46 tumours (59%), while 11 lesions (14.1%) showed no evidence of hypermethylation at any of the loci studied. Methylation at any or all of MGMT, P14 or P16 was significantly associated with APC methylation (p = 0.01). Those neoplasms with more than two methylated genes showed significantly fewer chromosomal abnormalities than adenomas with one or no methylated loci (p < 0.001). There was no association between specific individual chromosomal abnormalities, APC, KRAS or TP53 mutations and any pattern of methylation abnormality. We conclude that methylation abnormality is very common in pre-invasive colorectal neoplasia, and that high level methylation is associated with low level chromosomal instability.
Assuntos
Adenoma/genética , Aberrações Cromossômicas , Neoplasias Colorretais/genética , Genes Supressores de Tumor/fisiologia , Mutação Puntual/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/genética , Metilases de Modificação do DNA , Enzimas Reparadoras do DNA , Genes APC/fisiologia , Genes p16/fisiologia , Genes p53/genética , Humanos , Metilação , Proteína 1 Homóloga a MutL , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Hibridização de Ácido Nucleico/métodos , Fenótipo , Regiões Promotoras Genéticas/genética , Proteína Supressora de Tumor p14ARF/genética , Proteínas Supressoras de TumorRESUMO
Monoclonal antibody resistant (MAR) mutants (which escaped antibody-mediated neutralization) were selected from simian (W 3) and human (LN) isolates of simian virus 5 (SV 5), using monoclonal antibodies (MAbs) specific for antigenic sites 4 and 5 on the HN glycoprotein. Resistance correlated with an inability of the selecting antibody to bind with the respective MAR mutants. Sequence comparisons between parental and mutant HN proteins revealed multiple non-adjacent amino acid substitutions in the majority of MAR mutants. The same multiple substitutions were identified in mutants selected from both the LN and W 3 isolates of SV 5. Furthermore, different mutations on the primary sequence of the HN protein conferred resistance to the same MAb.
Assuntos
Proteína HN/química , Mutação , Respirovirus/química , Aminoácidos/química , Aminoácidos/genética , Animais , Anticorpos Monoclonais/imunologia , Clonagem Molecular , Análise Mutacional de DNA , Proteína HN/genética , Proteína HN/imunologia , Humanos , Testes de Neutralização , Respirovirus/genética , Respirovirus/imunologia , Células VeroRESUMO
The nucleotide sequence of the haemagglutinin-neuraminidase (HN) gene was determined for a simian (W3), human (LN) and two canine (CPI+/CPI-) isolates of simian virus 5 (SV5). A comparison of the predicted amino acid sequences revealed that the human and canine isolates varied from the simian isolate by 1.7% and 2.4% respectively. This lack of significant variation between the HN proteins of the four SV5 isolates suggests that insufficient differences have occurred between isolates to confine them to a specific host.