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

doi:10.1016/0304-3940(94)90128-7

Neuroscience Letters

Volume 174, Issue 1, 6 June 1994, Pages 97-100

https://doi.org/10.1016/0304-3940(94)90128-7 Get rights and content

Abstract

A major gene for familial early-ons et 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 βA4 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.

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Cited by (19)

The role of collagen type I α2 polymorphisms: intracranial aneurysms in Koreans
2009, Surgical Neurology
Citation Excerpt :
However, although the 3 SNPs studied by Yoneyama et al were found to be associated with the development of IAs, these associations were not replicated in the other populations. Genetic variants located in introns might influence phenotypes via transcription [1,5], but rs2621215 in intron 46 is distanced from the promoter and the intron 1 of COL1A. This may result in a spurious positive signal rather than a real polymorphism that affects disease susceptibility.
The COL1A2 is located on chromosome 7q22.1, and mutations in this gene have been associated with the development of IAs. In this study, we investigated whether the rs42524 and rs2621215 polymorphisms of the COL1A2 gene are associated with the development of cerebral aneurysms in the Korean population.
This was a hospital-based case control study conducted at Chonnam University Hospital, Gwangju, Korea. The study population consisted of 320 patients who had been treated for IA and 189 healthy hospital-based controls (angiographically negative for an IA). Two polymorphic loci were amplified by polymerase chain reaction, namely, rs42524 in exon 28 and rs2621215 in intron 46 of the COL1A2 gene, and analyzed by RFLP using HhaI or BfaI restriction enzymes, respectively.
The genotype frequencies of rs42524 in cases were 88.0%, 11.4%, and 0.6% for the GG, GC, and CC genotypes, respectively, and in controls were 88.9%, 10.0%, and 1.1%, respectively. Similarly, the genotype frequencies of rs2621515 in cases were 88.0%, 10.1%, and 0.2% for the TT, TG, and GG genotypes, respectively, and among controls were 92.1%, 7.9%, and 0%, respectively.
The rs2621215 SNP in intron 46 of the COL1A2 gene was found to be marginally associated with an increased risk of IA development in the Korean population examined. In contrast, rs42524 showed no association with an increased risk of IA development.
A polymorphic variant of the endoglin gene is associated with increased risk for intracranial aneurysms in a Korean population
2008, Surgical Neurology
Citation Excerpt :
Although the in/del in intron 7 has been found to be associated with the occurrence of intracranial disease, such as ICH and cerebral aneurysms [1,27], a more practical approach for the detection of a candidate gene for IAs would be analysis of coding nonsynonymous SNPs, which accompany amino acid substitutions. Genetic variants located in the intron might influence a phenotype via regulation of transcription [2,7]; however, the in/del in intron 7 is far away from the promoter and the first intron of the gene; this may result in a false-positive signal rather than a real polymorphism for disease susceptibility. The goal of this study was to determine the contribution of this polymorphism to the risk for IAs in a Korean population.
Endoglin is a component of the transforming growth factor-β receptor complex and is predominantly expressed on the cell surface of endothelial cells. It plays an important role in vascular growth and development. There have been conflicting reports on whether a polymorphic variant, in the endoglin gene, is associated with risk for IAs. In this study, we investigated whether polymorphisms of the endoglin gene are associated with the development of cerebral aneurysms in a Korean population.
This was a hospital-based, case-control study conducted at the Chonnam University Hospital, Gwangju, Korea. The study population consisted of 342 patients who had been treated for intracranial aneurysm and 253 healthy, hospital-based controls. Two polymorphic loci were amplified by polymerase chain reaction. The well-known in/del in intron 7 of the endoglin gene and the rs1800956 coding nonsynonymous SNP were amplified by PCR and analyzed by MADGE or the pyrosequencing system.
The endoglin insertion polymorphism was not associated with IAs in comparisons between cases and controls (OR, 0.11 [95% CI, 0.79-1.57] vs OR, 0.88 [95% CI, 0.50-1.56]). An association was found with rs1800956 in the heterozygous type (OR, 1.71); however, the association was not evident for the homozygous type. These differences were statistically significant. In addition, the C allele was significantly associated with an increased risk for IAs (OR, 1.73).
The rs1800956 (G/C transversion with D366H substitution, National Center for Biotechnology Information SNP database) of endoglin may play an important role in the pathogenesis of IAs in the Korean population. However, the in/del of intron 7 was not associated with an increased risk for IAs, which is consistent with the findings of previous reports.
c-Fos Is a Critical Mediator of Inflammatory-Mediated Repression of the Apical Sodium-Dependent Bile Acid Transporter
2006, Gastroenterology
Background & Aims: Ileal bile acid malabsorption is present in Crohn’s ileitis. The molecular mechanisms of regulation of the apical sodium-dependent bile acid transporter (ASBT) by inflammatory cytokines in vitro and in vivo are investigated.
Methods: Transient transfection studies of the human, mouse, and rat ASBT promoters and Northern analyses were performed in cells treated with the inflammatory cytokines and/or various activator protein-1 constructs. Rat ASBT promoter transgenic, wild-type, and c-fos–null mice were treated with indomethacin to assess the response to acute inflammation of the ileal mucosa.
Results: In Caco-2 cells, ASBT messenger RNA expression was reduced 65% after interleukin-1β treatment, while c-fos and c-jun were up-regulated 2-fold. Human ASBT promoter activity was enhanced by c-jun and repressed by a dominant negative c-jun, c-fos, or a dominant negative c-fos. Meanwhile, c-fos antisense treatment activated the human ASBT promoter 5-fold and not only abrogated interleukin-1β–mediated repression but led to a paradoxical increase in ASBT promoter activity. Indomethacin-induced acute ileitis led to repression of ASBT in wild-type mice and in the transgenic rat ASBT promoter reporter, while paradoxical activation of ASBT was seen in c-fos–null mice. Indomethacin-induced ileal injury was greater in the c-fos–null mice compared with the wild-type littermates.
Conclusions: Human, rat, and mouse ASBT is inhibited by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter.
Mutation analysis of the chromosome 14q24.3 dihydrolipoyl succinyltransferase (DLST) gene in patients with early-onset Alzheimer disease
1995, Neuroscience Letters
Linkage analysis studies have indicated that the chromosome band 14824.3 harbours a major gene for familial early-onset Alzheimer's disease (AD). Recently we localized the chromosome 14 AD gene (AD3) in the 6.4 cM interval between the markers D14S289 and D14S61. We mapped the gene encoding dihydrolipoyl succinyltransferase (DLST), the E2k component of human α-ketoglutarate dehydrogenase complex (KGDHC), in the AD3 candidate region using yeast artificial chromosomes (YACs). The DLST gene is a candidate for the AD3 gene since deficiencies in KGDHC activity have been observed in brain tissue and fibroblasts of AD patients. The 15 exons and the promoter region of the DLST gene were analysed for mutations in chromosome 14 linked AD cases and in two series of unrelated early-onset AD cases (onset age < 55 years). Sequence variations in intronic sequences (introns 3, 5 and 10) or silent mutations in exonic sequences (exons 8 and 14) were identified. However, no AD related mutations were observed, suggesting that the DLST gene is not the chromosome 14 AD3 gene.
Genes in early onset Alzheimer's disease: Implications for AD research
1994, Neurobiology of Aging
Immediate early genes, inducible transcription factors and stress kinases in Alzheimer's disease
2006, Immediate Early Genes in Sensory Processing, Cognitive Performance and Neurological Disorders

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Neuroscience Letters

Abstract

References (14)

The c-fos gene and early-onset familial Alzheimer's disease

Neurosci. Lett.

Positive and negative regulatory elements for the expression of the Alzheimer's disease amyloid precursor-encoding gene in mouse

Gene

Characterization of the 5′-end region and the first two exons of the β-protein precursor gene

Biochem. Biophys. Res. Commun.

The regulation and function of c-fos and other immediate early genes in the nervous system

Neuron

c-fos protein-like immunoreactivity: distribution in the human brain and over-expression in the hippocampus of patients with Alzheimer's disease

Neuroscience

Human c-fos oncogene mapped within chromosomal region 14q21–14q31

A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α₁-antichymotrypsin gene

Nature Genet.

Cited by (19)

The role of collagen type I α2 polymorphisms: intracranial aneurysms in Koreans

A polymorphic variant of the endoglin gene is associated with increased risk for intracranial aneurysms in a Korean population

c-Fos Is a Critical Mediator of Inflammatory-Mediated Repression of the Apical Sodium-Dependent Bile Acid Transporter

Mutation analysis of the chromosome 14q24.3 dihydrolipoyl succinyltransferase (DLST) gene in patients with early-onset Alzheimer disease

Genes in early onset Alzheimer's disease: Implications for AD research

Immediate early genes, inducible transcription factors and stress kinases in Alzheimer's disease

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

Abstract

Neurosci. Lett.

Gene

Biochem. Biophys. Res. Commun.

Neuron

Neuroscience

Human c-fos oncogene mapped within chromosomal region 14q21–14q31

A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α1-antichymotrypsin gene

Nature Genet.

A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α₁-antichymotrypsin gene