RESUMEN
In this study, we investigated the associations between single-nucleotide polymorphisms in GAB2 (rs2373115), GSK3B (rs6438552) and SORL1 (rs641120) and Alzheimer's disease (AD), both alone and in combination with the APOE*4 allele.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Proteínas del Citoesqueleto/genética , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Edad de Inicio , Anciano , Femenino , Humanos , Masculino , Factores de RiesgoRESUMEN
We report a 10-year-old boy with syndromic cleft lip and palate (CLP) and neuro-psychomotor developmental delay. Oligoarray comparative genomic hybridization (aCGH) detected an approximately 300 kb interstitial microduplication at 5p15.33 encompassing 5 protein-coding genes, including TERT and CLPTM1L, and two microRNA genes. Our findings suggest that the duplicated segment predisposes for cleft lip with or without cleft palate (CL/P), or any of the other phenotypic features presented by the patient. A gene coding a similar protein (CLPMT1) has been implicated in CLP etiology both through linkage studies and by a translocation disrupting the gene, indicating the possible involvement of CLPTM1L with CL/P. This is the first report of a possible connection between CLPTM1L and CLP.
Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos Par 5/genética , Labio Leporino/genética , Fisura del Paladar/genética , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Niño , Labio Leporino/diagnóstico , Fisura del Paladar/diagnóstico , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Humanos , Masculino , MicroARNs/genética , Fenotipo , Telomerasa/genéticaRESUMEN
In this study, we investigated the associations between single-nucleotide polymorphisms in GAB2 (rs2373115), GSK3B (rs6438552) and SORL1 (rs641120) and Alzheimer's disease (AD), both alone and in combination with the APOE*4 allele.
Asunto(s)
Anciano , Femenino , Humanos , Masculino , Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , /genética , Proteínas del Citoesqueleto/genética , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Edad de Inicio , Factores de RiesgoRESUMEN
OBJECTIVES: Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. METHODS: One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. RESULTS: Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2+/-210.5; 581.9+/-379.4; and 777.5+/-467.8 pg/l respectively; P<0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8+/-463.0; stable MCI, 724.0+/-343.4; P=0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR=3.0 CI(95%) [1.2-7.8], P=0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR=4.4 CI(95%) [1.6-12.1], P=0.004). CONCLUSION: Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.