Identification of compound heterozygous mutations of F11 gene in a pedigree affected with heriditary coagulation factor XI deficiency / 中华医学遗传学杂志

OBJECTIVE@#To identify potential mutations of F11 gene in a pedigree affected with hereditary coagulation factor XI (FXI) deficiency and explore its molecular pathogenesis.@*METHODS@#Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), coagulation factor VIII activity (FVIIIC), coagulation factor IX activity (FIXC), coagulation factor XI activity (FXIC), coagulation factor XII activity (FXIIC) and lupus anticoagulation (LA) of the proband and eight family members were determined. FXI antigen (FXIAg) was determined by enzyme-linked immunosorbent assay (ELISA). For the proband, potential mutations in the exons, flanking introns and 5'-, 3'-untranslated regions of the F11 gene were screened by direct DNA sequencing. The results were confirmed by reverse sequencing. Suspected mutations were detected in other family members. ClustalX-2.1-win and four online bioinformatic tools (PolyPhen-2, PROVEAN, SIFT, and Mutation Taster) were used to study the conservation and possible impact of the mutations. The structure of the mutational sites was processed with Swiss-PdbViewer.@*RESULTS@#The propositus had prolonged APTT (69.6 s), whose FXIC and FXIAg were reduced to 6.0% and 10.7%, respectively. Her mother, elder sister, one younger sister, little brother, daughter and son showed slightly prolonged APTT and moderate FXIC and FXIAg levels. Gene sequencing revealed that the propositus carried a heterozygous nonsense mutation c.738G>A (p.Trp228stop) in exon 7 and a heterozygous mutation c.1556G>C (p.Trp501Ser) in exon 13. Her mother, elder sister and daughter were heterozygous for the p.Trp228stop mutation, while one younger sister and little brother and son were heterozygous for p.Trp501Ser. Her husband and the youngest sister were of the wild type. Phylogenetic analysis suggested that Trp501 was highly conserved among all homologous species. The p.Trp501Ser was predicted to be "probably damaging","deleterious", "affect protein function" and "disease causing" corresponding to PolyPhen-2, PROVEAN, SIFT and Mutation Taster. Model analysis demonstrated that the non-polar Trp501 has two benzene rings, forming a hydrogen bond with Gln512 in the wild type. Once substituted by Ser501, the side chain may form another hydrogen bond with the benzene of His396. This may affect the normal space conformation and stability of FXI protein.@*CONCLUSION@#The compound heterozygous mutations of the F11 gene probably accounted for the low FXI concentration in this pedigree.

Prevalence of fasting blood glucose abnormality and associated factors analysis in health examination population above 18 years old in Beijing / 肠外与肠内营养

Objective: To study the fasting blood glucose level and associated factors relationship in physical examination population in Beijing. Methods: Totally 38 462 individuals who received physical examination from April 2006 through December 2007 in Peking Union Medical College Hospital physical examination center were enrolled in our study.We divided them into 8 groups according to the age,and the level of fasting blood glucose was tested.The relationship between BMI,age,sex and abnormity of blood glucose were analysed. Results: The incidences of overweight and obesity were 36.4% and 13.5%,respectively.The incidences of impaired fasting glucose and diabetes mellitus were 3.2% and 3.8%,respectively.The rate of abnormal glucose level increased with age and BMI.Compared to male,female persons had lower fasting blood glucose level and lower rate of abnormality(P =0.000).Compared to normal and thin population,overweight and obesity population had higher rate of fasting glucose abnormality(P