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L Farrer

Publications and source records attributed to L Farrer.

13 recordsLinked to original sources
PubMed2002

Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD.

We have analyzed the 5'-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 5' 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 age-matched 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) epsilon4 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-1beta and Abeta42, but that it is synergistically induced 3.2-fold over the wild-type PSEN2 by [IL-1beta+Abeta42]. 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.

5' Untranslated Regions↗
PubMed2001

Highly polymorphic short tandem repeat analyses clarify complex molecular test results.

Judicious application of highly polymorphic short tandem repeat (STR) analyses and modification of assay conditions readily distinguished nonparentage from true parentage, with occasional failure to transmit one parentally derived allele. These categories were resolved with a reliability of >99.9%, the standard applied to most DNA evidence presented in a U.S. court of law. While completing a single prenatal diagnosis submitted at 19 weeks gestation, the authors found that one polymorphic grandpaternal allele did not amplify, a duplicate control propositus' DNA sample had been switched by an outside laboratory, and recombination occurred in maternal meiosis within the mutant gene region. In two parentage cases with one available parent, a Y-linked STR or an autosomal STR was modified when transmitted to the offspring. In contrast, some apparently inconsistent results between parental DNA and offspring were resolved by purifying or diluting the original extracted DNA samples. Thus, the source of each complex molecular test result was characterized unambiguously by testing a sufficient number of highly polymorphic STR loci and by purifying or diluting troublesome DNA samples to diminish polymerase chain reaction amplification artifact.

Adult↗
PubMed1999

Identification of a polymorphic glutamic acid stretch in the alpha2B-adrenergic receptor and lack of linkage with essential hypertension.

Essential hypertension, a clinically significant elevation in blood pressure with no recognizable cause, is believed to be attributable to the collective effect of genetic predisposing factors in combination with specific environmental factors, such as diet and stress. Of the genetic causes, genes coding for proteins involved in blood pressure regulation, such as the alpha- and beta-adrenergic receptors, are obvious candidates. The alpha2-adrenergic receptor plays a key role in the sympathetic nervous system by mediating the effects of epinephrine and norepinephrine. To evaluate the potential role between the alpha2B receptor and essential hypertension, we scanned the alpha2B-receptor gene for genetic variation in 108 affected sibling pairs. The screening revealed two major forms of the receptor. They differ by the presence of either 9 or 12 glutamic acid residues in the acidic domain of the third cytoplasmic loop of the protein. Investigation of the pattern of this variation in hypertensive sibling pairs suggests that the alpha2B receptor locus does not contribute substantially to genetic susceptibility for essential hypertension.

Alleles↗
PubMed1999

Evidence for linkage between essential hypertension and a putative locus on human chromosome 17.

Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (P=0.0005) and refines the location of the blood pressure QTL.

Aged↗
PubMed1998

Absence of association between Alzheimer disease and the -491 regulatory region polymorphism of APOE.

A novel polymorphism (-491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the -491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE epsilon2/epsilon3/epsilon4 polymorphism.

Aged↗
PubMed1998

Analysis of the butyrylcholinesterase gene and nearby chromosome 3 markers in Alzheimer disease.

The K-variant of butyrylcholinesterase (BCHE-K) recently has been reported to be associated with Alzheimer disease (AD) in carriers of the epsilon4 allele of the apolipoprotein E (APOE) gene. We have re-examined the frequency of the BCHE-K allele in a large data set of both sporadic and familial cases of AD disease, and we have also examined the segregation of three genetic markers on chromosome 3 near BCHE . Our data neither support an association of BCHE-K with sporadic or familial AD, nor do they suggest the existence of another gene nearby on chromosome 3 as a common cause of familial AD.

Aged↗
PubMed1996

A novel mutation in the MITF gene causes Waardenburg syndrome type 2.

Mutations in the MITF gene on human chromosome 3 have been reported in families with Waardenburg Syndrome Type 2 (WS2), an autosomal dominant disorder responsible for a large proportion of congenital hearing loss. We examined 16 families with WS2 for mutations in the MITF gene. In one four-generation family, we found a novel two-base deletion in exon 6 of the MITF gene at nucleotide position 699. This mutation introduces a frame-shift and stop codon which leads to a truncation of the protein. This mutation is predicted to have phenotypic consequences not withstanding evidence of reduced penetrance and heterogeneity within the family studied.

Binding Sites↗
PubMed1994

[Mapping the gene for palmoplantar hyperkeratosis (thylosis) to chromosome 17 in the 17q12-q24 region].

Mapping of the genetic defect causing dominant palmoplantaris hyperkeratosis (PPHK) was continued based on the material of an extended Uzbek pedigree. No linkage between the PPHK gene and hypervariable DNA markers from 8p, 12p, 14q, and 22q were revealed. The study of PPHK gene linkage with DNA markers covering the entire length of 17th chromosome mapped the PPHK gene to 17q12-q24 and revealed close linkage with KRT10 and D17S800 loci (zero recombination frequency at a lod score > 7). The possible location of a PPHK mutation in one of the keratin genes mapped to the same region on the 17th chromosome is discussed.

Chromosome Mapping↗
PubMed1993

A 4.5-megabase yeast artificial chromosome contig from human chromosome 13q14.3 ordering 9 polymorphic microsatellites (22 sequence-tagged sites) tightly linked to the Wilson disease locus.

We have previously performed a genetic analysis of multiply affected families to map a locus responsible for Wilson disease (WND) to a 0.3-centimorgan (cM) region within chromosome 13q14.3, between D13S31 and D13S59. Here we describe the construction of a contig of approximately 4.5 Mb, which spans this region and extends from D13S25 to D13S59. This contig consists of 28 genomic yeast artificial chromosome (YAC) clones. Five critical crossover events have been defined in this interval in two unaffected (Centre d'Etudes du Polymorphisme Humain) and three WND families. The combination of sequence tagged site content mapping of YACs with both polymorphic and nonpolymorphic markers and recombination breakpoint mapping resulted in the following order of polymorphic markers: centromere-RB1-D13S25-AFM205vh2-D13S31-D13S22 7-D13S228-AFM238vc3-D13S133- AFM084xc5-D13S137-D13S169, D13S155-D13S59-telomere. The recombination/physical distance ratio varies from approximately 3000 kb per cM in the region between D13S31 and D13S25 to 6000 kb per cM in the region between D13S31 and D13S59. Three WND families exhibiting recombination between the disease locus and D13S31 or D13S59 were genotyped for additional markers in this region and further refined the location of the WND gene to between D13S155 and D13S133. Nine of the markers in this region of < 1 cM are polymorphic microsatellites (seven have observed heterozygosities of 70% or above) that will be extremely useful in prenatal and preclinical diagnosis of this disease. This physical map is an essential step in the isolation of the WND gene and is a framework for the identification of candidate genes.

Base Sequence↗
PubMed1992

Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14.

Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.

Aged↗
PubMed1989

Molecular genetics of familial Alzheimer's disease.

The molecular genetic strategies aimed at isolating and characterizing the defective gene(s) in familial Alzheimer's disease, the inherent limitations of the techniques and recent progress in the field are reviewed. Three independent groups have found an apparent linkage to chromosome 21 but two other groups have not, suggesting that familial Alzheimer's disease may be etiologically heterogeneous.

Alzheimer Disease↗
PubMed1989

Molecular genetics of familial Alzheimer's disease.

A proportion of cases of Alzheimer disease show familial aggregation with a pattern of vertical transmission compatible with autosomal dominant inheritance. Isolation of the genetic defect causing this form of Alzheimer disease, which may elucidate the biochemical mechanisms underlying the pathogenesis of the Alzheimer disease phenotype, can theoretically be achieved by first defining the chromosomal location of the disease gene(s) by classical genetic linkage studies in large families segregating this disorder. Subsequently, other cloning strategies can be applied to isolate the disease gene from the chromosomal region showing tight linkage to the disease phenotype. This paper reports some recent results of such studies, and discusses some of the potential confounding events which must be considered when approaching inherited neuropsychiatric disorders using these strategies.

Alzheimer Disease↗