Molecular bases of spinal muscular atrophy: the survival motor neuron gene

L'atròfia muscular espinal (AME) és una malaltia neuromuscular autosòmica recessiva caracteritzada per Ia degeneració i Ia pèrdua de Ies motoneurones de Ia banya anterior de Ia medul·la espinal. Les manifestacions clíniques més característiques són una debilitat proximal simètrica i una atròfia muscular progressiva. La identificació del gen SMN1 com a gen determinant de I'AME obre noves alternatives per a I'estudi de Ia malaltia. En Ia majoria dels pacients es detecta I'absència del gen SMN1 (ja sigui per deleció o per conversió), però també se n'han identificat mutacions puntuals en un petit percentatge. L'absència del gen SMN1 s'associa a un ampli espectre de manifestacions clíniques, que van des de formes congènites de Ia malaltia fins a casos asimptomàtics. Diferents factors modificadors, com el nombre de còpies del gen SMN2 – el gen homòleg present tant en controls com en malalts – poden modificar el fenotip i a Ia vegada ser útils per investigar un tractament eficaç. Tot i que el gen SMN s'expressa en diferents poblacions neuronals, només Ies motoneurones són Ies responsables de Ies manifestacions de Ia malaltia. La proteïna SMN forma part d'un complex amb altres proteïnes que participen en Ia reacció d'empalmament i aquesta funció, essencial per a totes Ies cèl·lules, sembla ser crítica per a Ies neurones motores. Cal aprofundir en I'estudi dels mecanismes que condueixen a I'atròfia muscular espinal.Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration and loss of motor neurons of the anterior horn of the spinal cord. The clinical manifestations include proximal symmetric weakness and progressive muscle atrophy. The identification of the SMN1 gene as determinant of SMA has opened alternative ways of studying the disease. Absence of SMN1 (either by deletion or conversion) was detected in the majority of patients and subtle mutations were described in a minority. SMN1 absence was associated with a wide spectrum of manifestations, from congenital disease to asymptomatic cases. Modifier factors, such as the number of copies of SMN2, its homologous copy present in all patients, could influence the phenotype and help to find a treatment for the disease. The SMN gene is expressed in various neuronal populations, although only motor neurons are responsible for the manifestations of the disease. The SMN protein is part of a complex with various proteins involved in the splicing reaction. This apparently essential function of all cells is critical for motor neurons, and warrants further research to elucidate the mechanisms of disease

Allelic and genotypic associations of DRD2 Taq I A polymorphism with heroin dependence in Spanish subjects: a case control study

Background: Conflicting associations with heroin dependence have been found involving the A1 allele of dopamine D2 receptor gene ( DRD2) TaqI A polymorphism. Methods: We compared two samples of unrelated Spanish individuals, all of European origin: 281 methadone-maintained heroin-dependent patients ( 207 males and 74 females) who frequently used non-opioid substances, and 145 control subjects ( 98 males and 47 females). Results: The A1-A1 genotype was detected in 7.1% of patients and 1.4% of controls ( P = 0.011, odds ratio = 5.48, 95% CI 1.26-23.78). Although the A1 allele was not associated with heroin dependence in the entire sample, the frequency of A1 allele was higher in male patients than in male controls ( 24.4% vs. 16.3%, P = 0.024, odds ratio = 1.65, 95% CI 1.07-2.57). A logistic regression analysis showed an interaction between DRD2 alleles and gender ( odds ratio = 1.77, 95% CI 1.15-2.70). Conclusion: Our results indicate that, in Spanish individuals, genotypes of the DRD2 TaqI A polymorphism contribute to variations in the risk of heroin dependence, while single alleles contribute only in males

Association of thymidylate synthase polymorphisms with acute pancreatitis and/or peripheral neuropathy in HIV-infected patients on Stavudine-Based Therapy

BACKGROUND: Low expression thymidylate synthase (TS) polymorphism has been associated with increased stavudine triphosphate intracellular (d4T-TP) levels and the lipodystrophy syndrome. The use of d4T has been associated with acute pancreatitis and peripheral neuropathy. However, no relationship has ever been proved between TS polymorphisms and pancreatitis and/or peripheral neuropathy. METHODS: We performed a case-control study to assess the relationship of TS and methylene-tetrahydrofolate reductase (MTHFR) gene polymorphisms with acute pancreatitis and/or peripheral neuropathy in patients exposed to d4T. Student's t test, Pearson's correlations, one-way ANOVA with Bonferroni correction and stepwise logistic regression analyses were done. RESULTS: Forty-three cases and 129 controls were studied. Eight patients (18.6%) had acute pancreatitis, and 35 (81.4%) had peripheral neuropathy. Prior AIDS was more frequent in cases than in controls (OR = 2.36; 95%CI 1.10-5.07, P = 0.0247). L7ow expression TS and MTHFR genotype associated with increased activity were more frequent in patients with acute pancreatitis and/or peripheral neuropathy than in controls (72.1% vs. 46.5%, OR = 2.97; 95%CI: 1.33-6.90, P = 0.0062, and 79.1% vs. 56.6%, OR = 2.90, 95%CI: 1.23-7.41, P = 0.0142, respectively). Independent positive or negative predictors for the development of d4T-associated pancreatitis and/or peripheral neuropathy were: combined TS and MTHFR genotypes (reference: A+A; P = 0.002; ORA+B = 0.34 [95%CI: 0.08 to 1.44], ORB+A = 3.38 [95%CI: 1.33 to 8.57], ORB+B = 1.13 [95%CI: 0.34 to 3.71]), nadir CD4 cell count >200 cells/mm(3) (OR = 0.38; 95%CI: 0.17-0.86, P = 0.021), and HALS (OR = 0.39 95%CI: 0.18-0.85, P = 0.018). CONCLUSIONS: Low expression TS plus a MTHFR genotype associated with increased activity is associated with the development of peripheral neuropathy in d4T-exposed patients

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients.

Purpose To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). Methods Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method. Results HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53-3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): 'A+A'; OR for 'A+B' vs. ref.: 1.39 [0.69-2.80]; OR for 'B+A' vs. ref.: 2.16 [1.22-3.83]; OR for 'B+B' vs. ref.: 3.13, 95%CI: 1.54-6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56-4.14, P = 0.001), (c) use of EFV (1.10 [1.00-1.21], P = 0.008, per year of use). Conclusion HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine

Molecular bases of spinal muscular atrophy: the survival motor neuron gene

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by regeneration and loss of motor neurons of the anterior horn of the spinal cord. The clinical manifestations include proximal symmetric weakness and progressive muscle atrophy. The identification of the SMN1 gene as determinant of SMA has opened alternative ways of studying the disease. Absence of SMN1 (either by deletion or conversion) was detected in the majority of patients and subtle mutations were described in a minority. SMN1 absence was associated with a wide spectrum of manifestations, from congenital disease to asymptomatic cases. Modifier factors, such as the number of copies of SMN2, its homologous copy present in all patients, could influence the phenotype and help to find a treatment for the disease. The SMN gene is expressed in various neuronal populations, although only motor neurons are responsible for the manifestations of the disease. The SMN protein is part of a complex with various proteins involved in the splicing reaction. This apparently essential function of all cells is critical for motor neurons, and warrants further research to elucidate the mechanisms of disease.L'atròfia muscular espinal (AME) és una malaltia neuromuscular autosòmica recessiva caracteritzada per Ia degeneració i Ia pèrdua de Ies motoneurones de Ia banya anterior de Ia medul·la espinal. Les manifestacions clíniques més característiques són una debilitat proximal simètrica i una atròfia muscular progressiva. La identificació del gen SMN1 com a gen determinant de I'AME obre noves alternatives per a I'estudi de Ia malaltia. En Ia majoria dels pacients es detecta I'absència del gen SMN1 (ja sigui per deleció o per conversió), però també se n'han identificat mutacions puntuals en un petit percentatge. L'absència del gen SMN1 s'associa a un ampli espectre de manifestacions clíniques, que van des de formes congènites de Ia malaltia fins a casos asimptomàtics. Diferents factors modificadors, com el nombre de còpies del gen SMN2 - el gen homòleg present tant en controls com en malalts - poden modificar el fenotip i a Ia vegada ser útils per investigar un tractament eficaç. Tot i que el gen SMN s'expressa en diferents poblacions neuronals, només Ies motoneurones són Ies responsables de Ies manifestacions de Ia malaltia. La proteïna SMN forma part d'un complex amb altres proteïnes que participen en Ia reacció d'empalmament i aquesta funció, essencial per a totes Ies cèl·lules, sembla ser crítica per a Ies neurones motores. Cal aprofundir en I'estudi dels mecanismes que condueixen a I'atròfia muscular espinal

Molecular bases of spinal muscular atrophy: the survival motor neuron gene

L'atròfia muscular espinal (AME) és una malaltia neuromuscular autosòmica recessiva caracteritzada per Ia degeneració i Ia pèrdua de Ies motoneurones de Ia banya anterior de Ia medul·la espinal. Les manifestacions clíniques més característiques són una debilitat proximal simètrica i una atròfia muscular progressiva. La identificació del gen SMN1 com a gen determinant de I'AME obre noves alternatives per a I'estudi de Ia malaltia. En Ia majoria dels pacients es detecta I'absència del gen SMN1 (ja sigui per deleció o per conversió), però també se n'han identificat mutacions puntuals en un petit percentatge. L'absència del gen SMN1 s'associa a un ampli espectre de manifestacions clíniques, que van des de formes congènites de Ia malaltia fins a casos asimptomàtics. Diferents factors modificadors, com el nombre de còpies del gen SMN2 el gen homòleg present tant en controls com en malalts poden modificar el fenotip i a Ia vegada ser útils per investigar un tractament eficaç. Tot i que el gen SMN s'expressa en diferents poblacions neuronals, només Ies motoneurones són Ies responsables de Ies manifestacions de Ia malaltia. La proteïna SMN forma part d'un complex amb altres proteïnes que participen en Ia reacció d'empalmament i aquesta funció, essencial per a totes Ies cèl·lules, sembla ser crítica per a Ies neurones motores. Cal aprofundir en I'estudi dels mecanismes que condueixen a I'atròfia muscular espinal.Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration and loss of motor neurons of the anterior horn of the spinal cord. The clinical manifestations include proximal symmetric weakness and progressive muscle atrophy. The identification of the SMN1 gene as determinant of SMA has opened alternative ways of studying the disease. Absence of SMN1 (either by deletion or conversion) was detected in the majority of patients and subtle mutations were described in a minority. SMN1 absence was associated with a wide spectrum of manifestations, from congenital disease to asymptomatic cases. Modifier factors, such as the number of copies of SMN2, its homologous copy present in all patients, could influence the phenotype and help to find a treatment for the disease. The SMN gene is expressed in various neuronal populations, although only motor neurons are responsible for the manifestations of the disease. The SMN protein is part of a complex with various proteins involved in the splicing reaction. This apparently essential function of all cells is critical for motor neurons, and warrants further research to elucidate the mechanisms of disease

Errors congènits del metabolisme (ECM).

La terminologia i el concepte d'Error Congènit del Metabolisme (ECM), van ser establerts per A. Garrod a principis de segle. Avui día sabem que estan causats per errors o mutacions en els gens. Degut a la naturalesa del nostre codi genètic, segons el qual les instruccions del DNA són traduïdes a un producte gènic, les proteïnes, que seran les encarregades d'executar-lo; les mutacions del DNA es tradueixen en proteïnes anòmales amb la corresponent..

A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12

Background: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. Results: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (Preplication=0.042; Ppooled=5.523x10-03; OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (Preplication=0.039; Ppooled=6.985x10-5; OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance. Conclusions: We have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction