RESUMEN
G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5.
Asunto(s)
Quinasa 5 del Receptor Acoplado a Proteína-G/genética , Predisposición Genética a la Enfermedad/genética , Síndrome de Heterotaxia/genética , Mutación con Pérdida de Función , Secuencia de Aminoácidos , Animales , Embrión no Mamífero/embriología , Embrión no Mamífero/metabolismo , Femenino , Frecuencia de los Genes , Células HEK293 , Síndrome de Heterotaxia/fisiopatología , Humanos , Hibridación in Situ , Masculino , Polimorfismo de Nucleótido Simple , Homología de Secuencia de Aminoácido , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
OBJECTIVE: What are the differences between the occurrence of menopausal symptoms in German women, migrant Chinese women in Germany and Chinese women in their native country? Can these potential discrepancies be explained by sociocultural differences? What are the differences in menopausal symptoms in connection with the consumption of soya? PATIENT STUDY GROUP AND METHODS: Cross-sectional study 2005-2008. Survey of three groups of women aged between 45 and 60 years (native German women in Berlin, migrant Chinese women in several German cities, Chinese women in Beijing) with an evaluated set of questionnaires surveying socio-demographic data, use of hormone therapy, migration/acculturation, MRS II and other areas. RESULTS: A total of 2,109 questionnaires were sent out and a 41 % response rate was achieved, although this varied greatly across the three individual study groups. The results of the MRS II factor analysis were almost identical for German women and migrant Chinese women, but there were some differences in content compared to the Chinese study group. Chinese women surveyed in Beijing reported severe symptoms significantly less frequently in all three symptom groups (factors) of MRS II than the German women and the migrant Chinese women, but the values from the German women and migrant Chinese women surveyed are relatively similar. In all three study groups there are no significant differences in the stated severity of the symptoms, regardless of whether soya is consumed frequently or less frequently. CONCLUSION: The question whether the differences found are solely cultural or migration-related must be examined in further studies. The special experiences and situation in life of migrant women should be taken into particular account by attending physicians during the care and treatment of women in this phase of life.
