Relative deficiency of transcription factors associated with methylation is responsible for the lack of AR promoter function in most of AR-negative cell lines. Mutations in the AR gene are present in the cells that express the AR but are androgen-independent.

No abstract

No abstract

A significant proportion of early onset Alzheimer's disease (AD) is caused by mutations in human genes for amyloid precursor protein (APP), presenilins 1 and 2 (PSEN1,2). AD associated mutations in PSEN1,2 genes alter the gamma-secretase cleavage activity of APP resulting in increased production of amyloidogenic Abeta42. PSEN dependent intramembrane proteolysis was described as an important step required for cleavage of Notch receptors, Notch-dependent signal transduction, and processing of other proteins. It is still unclear whether presenilins are unusual intramembrane proteases or they are necessary cofactors of gamma-secretase cleavage of APP and Notch. Identification of other proteins similar to presenilins may resolve this dilemma. We describe here the identification of novel families of genes encoding polytopic transmembrane proteins of Eukaryotes (IMPASes) and Arachaea(membrases). These proteins have a predicted structure similar to presenilins. The amino acid similarity is significant in domains carrying invariant amino acid residues, which are critical in specific presenilin-regulated endoproteolysis. Many members of the IMPAS family have protease associated domains (PA) typical of proteases. We identified and cloned five human IMPAS genes. Expression analysis of the hIMP1 gene (located on chromosome 20) was performed in human cell tissues and transfected cell cultures. The data demonstrate that a conservative class of putative protease-related polytopic proteins related to presenilins exists in multicellular eukaryotes and microorganisms.

We have analyzed the 5Ј-upstream promoter region of the presenilin 2 gene (PSEN2) for regulatory elements and examined Alzheimer disease (AD) patients and non-demented individuals for polymorphisms in the 5Ј upstream promoter region of the PSEN2 gene. Direct sequencing analysis detected a common single adenine (A) nucleotide deletion polymorphism in the upstream promoter region of the PSEN2 gene. Examination of cohorts of AD patients and agematched control individuals revealed no statistically significant differences in the frequency of this polymorphism when compared with the total sample of AD patients and control individuals. However, subgroup and regression analysis suggested that the relatively rare −A/−A genotype increases risk of AD among subjects lacking apolipoprotein E (APOE) ⑀4 and among persons ages 65 years and younger. DNA sequence and DNA-protein binding analysis demonstrated that this mutation negates binding with putative repressor transcription factor (TF), interferon regulatory factor 2 (IRF2), in nuclear extracts prepared from the aged human brain neocortex. However this mutation creates a potential regulatory element, C/EBPbeta, that is responsive to pro-inflammatory (PI) induction. The expression activity assay with luciferase reporter gene into normal human neural progenitor cells in primary culture shows that the mutant PSEN2 regulatory region exhibits a 1.8-fold higher level of basal expression and is sensitive to IL−1␤ and A␤42, but that it is synergistically induced 3.2-fold over the wild-type PSEN2 by [IL−1␤+A␤42]. These results suggest that under Pl and oxygen stress conditions relatively minor variations in PSEN2 promoter DNA sequence structure can enhance PSEN2 gene expression and that consequently these may play a role in the induction and/or proliferation of a Pl response in AD brain.

Cataract is one of the major causes of blindness in humans. We describe here an autosomal dominant polymorphic congenital cataract (PCC) which is characterised by wide variations in phenotype of non-nuclear lens opacities, even among affected members of the same family. PCC families included a large, unique pedigree (254 members, 103 affected individuals), and genetic linkage was conducted using a variety of polymorphic markers. Evidence for linkage was found for chromosome 2q33-35 with PCC mapping near D2S72 and TNP1. A tri-nucleotide microsatellite marker for gamma-crystallin B gene (CRYG1) was found to co-segregate with PCC and yielded a maximum lod score of 10.62 at (theta = 0). A multipoint analysis demonstrated that the most probable location of the PCC gene was within an 8 cM genetic interval containing the gamma-crystallin gene cluster. These data provide strong evidence of the existence of an autosomal dominant mutation for PCC in or near the gamma-crystallin gene cluster. This defect is characterised by complete penetrance but variable expression of the cataract phenotype. Our study also suggests that non-nuclear human cataracts might be caused by some abnormality in gamma-crystallin genes.

Associations of BDNF Val66Met polymorphism with such components of executive functions as verbal fluency, working memory, attention set shifting, and response inhibition were evaluated. A total of 401 healthy volunteers were genotyped. The effect of polymorphism on working memory during the counting test was detected. The test performance in heterozygotic carriers was much worse than in homozygotic ones. Individuals with the MetMet genotype demonstrated the best results, presumably due to molecular mechanisms compensating for the neuropeptide secretion deficiency.

No abstract