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H Backhovens

Publications and source records attributed to H Backhovens.

At least 37 records · Page 2Linked to original sources
PubMed1995

Genetic and physical characterization of the early-onset Alzheimer's disease AD3 locus on chromosome 14q24.3.

Genetic linkage studies have provided significant evidence that a major gene defect, AD3, for familial early-onset Alzheimer's disease (EOAD) is located at chromosome 14q24.3, between the short tandem repeat (STR) markers D14S52 and D14S53 defining a genetic size of 22.7 cM for the AD3 candidate region. We constructed a physical map of the AD3 region using yeast artificial chromosomes (YACs) selected from both the CEPH and megaCEPH YAC libraries using the AD3 linked STR markers as well as new sequence-tagged sites (STSs) designed based on YAC terminal sequences. The YAC map is contiguous in the region between D14S258 and D14S53, a region of 8.2 cM, and has an estimated physical size of 4-8 Mb. The YAC contig map was used as a framework to localize three known genes, a pseudogene and two brain expressed sequence tags (ESTs). Linkage analysis studies in two Belgian chromosome 14 EOAD families AD/A and AD/B, identified obligate recombinants in family AD/A with D14S289 and D14S61 reducing the genetic size of the candidate AD3 region substantially. The minimal AD3 candidate region measured 6.4 cM on the genetic map and is contained within six overlapping megaCEPH YACs that covered a physical distance estimated between 2 and 6 Mb. These YACs as well as other YACs in the YAC contig map are valuable resources in gene cloning efforts or genomic sequencing experiments aiming at isolating the AD3 gene.

Age of Onset↗
PubMed1994

Genetic analysis of the cellular oncogene fos in patients with chromosome 14 encoded Alzheimer's disease.

A major gene for familial early-onset Alzheimer's disease (AD) has been localised to chromosome 14q24.3. The c-fos gene (FOS), localised to 14q24.3-q31, is a candidate for the AD gene since it may be involved in the transcription regulation of the amyloid precursor protein gene (APP). Part of APP codes for the beta A4 amyloid present in AD brain lesions. We analyzed linkage of AD in the 2 early-onset AD families. AD/A and AD/B, using a polymerase chain reaction (PCR) based assay for a restriction fragment length polymorphism (RFLP). The RFLP is detected in BstNI digested DNA and is located near the 3' end of FOS. No obligate recombinants were detected. The 4 exons of FOS were sequenced in one pathologically confirmed AD patient in each family. No exonic mutations were found. Two intronic sequence variations were observed, one in intron 2 and one in intron 3. The intron 2 variation did not segregate with AD. The intron 3 variation which is a single G insertion was used in linkage studies in families AD/A and AD/B and showed conclusive linkage in both families in the absence of recombinants. Therefore, FOS cannot yet be excluded as a candidate gene for AD in these families since mutations may be present in regulatory sequences.

Alzheimer Disease↗
PubMed1994

APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease.

A recent study has demonstrated an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (AD). Also, in late-onset AD families linked to chromosome 19, the onset age decreased when the number of APOE*4 alleles increased. A similar effect of the APOE*4 genotype was observed in early-onset AD families linked to mutations in the APP gene located on chromosome 21. We assessed whether the APOE genotype had an influence on the age of onset of AD in chromosome 14 linked early-onset AD families. No significant effect of the APOE genotype on onset age could be detected.

Age of Onset↗
PubMed1994

A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21.

Linkage of Alzheimer disease (AD) to DNA markers on chromosomes 14, 19, and 21 was studied in 10 families in which the disease was apparently inherited as an autosomal dominant trait. Families were derived from a Dutch population-based epidemiologic study of early-onset AD. Although in all probands the onset of AD was at or before age 65 years, the mean age at onset was after age 65 years in four families (referred to as "LOAD"). Among the six families with early-onset AD (referred to as "EOAD," i.e., mean age of onset of AD of relatives was at or before age 65 years), conclusive linkage to 14q24.3 was found in one family with a very early onset (around 47 years), while linkage to the same region was excluded in two other families. For the LOAD families, predominantly negative lod scores were obtained, and the overall lod score excluded linkage to chromosome 14. The results with markers on chromosome 19 and chromosome 21 were not conclusive for EOAD and LOAD. The findings of our study confirm genetic heterogeneity within familial EOAD.

Aged↗
PubMed1992

Unique sequence homology in the pericentromeric regions of the long arms of chromosomes 13 and 21.

We previously isolated two polymorphic chromosome 21q probes, pVC1.21c (D21S190) and pVC1.34a (D21S149), localized in 21qcen-21q21.2. In addition, pVC1.21c recognized a sequence in 21q22.1-q22.2 and both probes cross-hybridized with non-chromosome-21 sequences. In this study we refined the proximal 21q locations of probes pVC1.21c and pVC1.34a to 21q11.1 and demonstrated that they recognize sequences on chromosome 13 but not on chromosomes 14, 15, and 22. Furthermore, the polymorphisms associated with the two loci were assigned to pericentromeric 13q for pVC1.34a and distal 21q for pVC1.21c. Our results are indicative of a region of unique sequence homology in the pericentromeric region of the long arms of chromosomes 13 and 21.

Blotting, Southern↗
PubMed1992

Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3.

Genetic linkage studies with chromosome 21 DNA markers and mutation analysis of the beta-amyloid protein precursor gene located in 21q21.3 have indicated that early-onset Alzheimer's disease (EOAD) is a heterogeneous disorder for which at least one other chromosomal locus exists. We examined two extended histopathologically confirmed EOAD pedigrees, AD/A and AD/B, with highly informative short tandem repeat (STR) polymorphisms and found complete linkage of the disease to a (CA)n dinucleotide repeat polymorphism at locus D14S43 in 14q24.3 (Zmax = 13.25 at theta = 0.0). Using additional chromosome 14 STR polymorphisms we were able to delineate the region containing the EOAD gene to an area of, at most, 8.9 centiMorgans between D14S42 and D14S53, flanking D14S43 on both sides.

Adult↗
PubMed1991

Screening for the beta-amyloid precursor protein mutation (APP717: Val----Ile) in extended pedigrees with early onset Alzheimer's disease.

Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene (the exons which encode the beta-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.

Alzheimer Disease↗
PubMed1991

Identification of chromosome 21 DNA polymorphisms for genetic studies in Alzheimer's disease and Down syndrome.

Linkage studies in families with presenile onset of Alzheimer's disease (AD) indicated the presence of a predisposing gene on the proximal long arm of chromosome 21. We mapped four new loci in the candidate AD region using somatic cell hybrids. For three of the four loci, several restriction fragment length polymorphisms were found; for one locus, a multiallelic (CA)n dinucleotide polymorphism was detected. Preliminary genetic mapping of the new polymorphic loci relative to the AD-linked loci was obtained in a reference pedigree. In addition, we used the (CA)n dinucleotide polymorphism to reconstruct the non-disjunction event in a Down syndrome (DS) patient whose mother died of familial AD.

Alzheimer Disease↗
PubMed1991

Subregional localization of the chromosome 21 loci D21S24 and D21S26 using physical mapping techniques.

We were able to refine the chromosomal position of two existing marker loci, using an extended chromosome 21 somatic cell hybrid panel. The locus D21S26 mapped in the region 21q11.2-q21.1, and the locus D21S24 in 21q22.1-q22.2. Physical and genetic analysis indicated that D21S26 is tightly linked to D21S13 and D21S16, two markers previously linked to familial Alzheimer's disease.

Alzheimer Disease↗
PubMed1990

Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder.

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

Alzheimer Disease↗
PubMed1990

Study of the origin of nondisjunction in a family with two cases of Down syndrome using cytogenetic and molecular polymorphisms.

We analyzed the possibility of inherited predisposition to nondisjunction in a family with two cases of Down syndrome using restriction fragment length polymorphisms and cytogenetic heteromorphisms. In both patients the extra chromosome 21 was the result of a nondisjunction event at first meiotic division in the mother. Since both patients are maternally related, genetic predisposition cannot be excluded in this family.

Blotting, Southern↗
PubMed1990

Physical mapping of chromosome 21 DNA markers in Alzheimer's disease region using somatic cell hybrids.

From a chromosome 21 phage library, we selected 10 clones located proximal of the senile plaque amyloid precursor protein gene. Since a locus for Alzheimer's disease (AD) has been localized in the pericentromeric region of chromosome 21, the selected phage clones are potential candidate probes for genetic analysis of AD. In this study, we subcloned single-copy fragments of the selected phage clones, refined their physical localization, and examined their chromosomal distribution in relation to their position on chromosome 21. The results indicated that the phage clones are identifying nine chromosome 21 loci, which, if polymorphic, may be helpful in localizing the AD locus more precisely. Moreover, since all phage clones are located close to the centromere of chromosome 21, they can be used to determine the parental origin of nondisjunction in trisomy 21 with high reliability.

Alzheimer Disease↗
PubMed1990

The pericentromeric 21 DNA marker pGSM21 (D21S13) contains an expressed HTF island.

The DNA marker locus D21S13, localized in the 21q11.1-q21 region, has been closely linked to familial Alzheimer's disease. We constructed a physical map of 1.7 Mb around D21S13 using probes pGSM21 and pGSE9. The results indicated that pGSM21 contains recognition sites for at least three rare-cutting restriction enzymes. The clustering of rare-cutting restriction sites is indicative of the presence of an HTF (HpaII tiny fragment) island. Restriction site mapping and methylation analysis proved that pGSM21 contains a methylation-free HTF island. Furthermore, a cDNA correlate has been isolated confirming that pGSM21 is part of an expressed sequence. Today, the gene associated with pGSM21 is the gene closest to the centromere on the 21q arm.

Chromosomes, Human, Pair 21↗
PubMed1989

Selection of human chromosome 21-specific DNA probes for genetic analysis in Alzheimer's dementia and Down syndrome.

We used a mouse-human somatic cell hybrid to construct a chromosome 21-enriched library in phage vector EMBL4. In all, 35 phage clones containing human inserts were identified by differential screening with total human and mouse DNA. Whole recombinant phages were regionally mapped on chromosome 21 by Southern blot analysis using competitive hybridisation conditions to block repetitive sequences. Ten phage clones mapped proximal to a translocation breakpoint in band 21q21.2, while 25 mapped distal to this point. Three of the phage clones identify restriction fragment length polymorphisms. Polymorphic chromosome 21 markers may be useful in the genetic analysis of Alzheimer's dementia and Down syndrome.

Alzheimer Disease↗
PubMed1989

Linkage analysis of the Duffy blood group marker with several chromosome 1 genes in an extended pedigree with Charcot-Marie-Tooth disease.

We have recently demonstrated tight linkage of the Duffy blood group marker to the alpha-spectrin gene in an extended pedigree with Charcot-Marie-Tooth neuropathy. To determine a more precise location of the Duffy blood group locus on the chromosome 1 map we have tested several more chromosome 1 genes for linkage with this marker. We found suggestive linkage with the antithrombin III and apolipoprotein A2 genes and conclusive linkage with the gene coding for beta-nerve growth factor.

Blood Group Antigens↗