Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families.

Nyström‐Lahti, Minna; Sistonen, P; Mecklin∥, Jukka–Pekka; Pylkkänen, Lea; Aaltonen, Lauri A.; Järvinen, Heikki; Weissenbach, Jean; Chapelle, Albert de la; Peltomäki, Païvi

doi:10.1073/pnas.91.13.6054

Cited by 74 publications

(38 citation statements)

References 20 publications

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“…This is a relatively small area considering that the possible ancestral AD mutation(s) was introduced into the population 15-25 generations ago, in which case the extended haplotypes should be found approximately 1-12 cM around the disease gene. 33,34 According to the haplotype estimation analysis with markers D13S292 and D13S787, there may exist more than one diseaseassociated haplotype. Therefore, only the chromosomal regions displaying the strongest association can be Linkage disequilibrium in Alzheimer's disease M Hiltunen et al t Table 3 Linkage disequilibrium results with the microsatellite markers D13S292 and D13S787 after stratification of the AD and control (C) groups according to female, familial and female/familial data observed, while the flanking regions of disease-associated haplotypes disappear due to the populationbased sampling strategy used.…”

Section: Discussionmentioning

confidence: 99%

Linkage disequilibrium in the 13q12 region in Finnish late onset Alzheimer's disease patients

et al. 1999

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Alzheimer's disease (AD) is a complex neurodegenerative disorder, for which several diseaseassociated loci have been located on different chromosomes. We have used a population-based linkage disequilibrium mapping approach in order to find potential AD-associated loci on chromosome 13. To avoid population stratification, late onset AD patients and age-matched controls were carefully chosen from the same geographical area in Eastern Finland, where the population is mainly descended from a small group of original founders. During the initial screening with chromosome 13-specific microsatellite markers, tetranucleotide marker D13S787 was found to be in linkage disequilibrium in the 13q12 region. Screening this region with additional microsatellite markers revealed that marker D13S292 was also significantly associated with AD. Stratification of the AD patients and controls into groups according to apolipoprotein E, sex, and familial/sporadic status indicated that the 13q12 locus was associated with female familial AD patients regardless of ApoE genotype. Based on the physical data from the region 13q12, markers D13S292 and D13S787 were estimated to reside in a 810 kb long YAC clone 754h7 together with two infant brain-derived ESTs and the H,K-ATPase α-subunit protein gene (ATP1AL1). The localisation of these sequences at the linkage disequilibrium region suggests that they may be candidate genes involved in a sexspecific effect during development of AD.

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Section: Discussionmentioning

confidence: 99%

Linkage disequilibrium in the 13q12 region in Finnish late onset Alzheimer's disease patients

et al. 1999

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“…The population of this geographical region has previously shown founder effects in studies with monogenic diseases. 21,28 When looking even more carefully, two of the Savo families from neighboring parishes shared a long haplotype of 8 cM, comprising both associated haplotypes 3-1 and 3-2-8, as described above. Two families with the 3-2-8 haplotype originate from western Finland.…”

Section: Haplotype Association In 6qmentioning

confidence: 91%

“…This region is also known for a previously characterized founder effect for the MLH1 susceptibility gene for colon cancer. 21 Altogether, 38 patients and 68 relatives were collected. To allow the unambiguous reconstruction of haplotypes, available parents or alternatively spouses and offspring were collected.…”

Section: Singleton Triosmentioning

confidence: 99%

Haplotype associations define target regions for susceptibility loci in systemic lupus erythematosus

Koskenmies

Widén²,

Onkamo

et al. 2004

Eur J Hum Genet

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse and variable clinical manifestations. The etiology of SLE is still unknown, but both environmental and genetic factors are involved. Recent genome-wide scans and candidate genes studies in different ethnic groups have already suggested susceptibility loci for SLE, but most of the genetic component remains unexplained. We have previously conducted a genome-wide scan in 35 Finnish families multiply affected with SLE. With 417 microsatellite markers, we detected suggestive linkage in regions on chromosomes 6q and 14q as well as HLA on 6p. The 14q locus has also been implicated in three previous genome scans on SLE, whereas a partially overlapping region on 6q was implicated in one previous study. In an effort to obtain additional evidence for susceptibility loci on 6q and 14q and in order to refine their positions, we performed fine mapping at 1 cM density across the suggestive regions of linkage. Our results show evidence for excess sharing of a haplotype on 14q and excess transmission of a haplotype on 6q. Our results are compatible with the idea of a founder effect for susceptibility genes in SLE in central eastern Finland and suggest a path to the isolation of the putative susceptibility genes.

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“…D3S1277 lies between D3S1561 and D3S1611, and these three microsatellites and D3S1029 were used to study hMLH1. 29,30 An Alu polymorphism in intron 1 of the p53 gene and D17S261 were used to study LOH at p53. 31,32 LOH at the APC gene was studied with D5S346, located 30 to 70 kb downstream from APC and D5S107, which is also located on 5q.…”

Section: Methodsmentioning

confidence: 99%

Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis

et al. 1998

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DNA mismatch repair is an important mechanism involved in maintaining the fidelity of genomic DNA. Defective DNA mismatch repair is implicated in a variety of gastrointestinal and other tumors; however, its role in hepatocellular carcinoma (HCC) has not been assessed. Formalin-fixed, paraffin-embedded archival pathology tissues from 46 primary liver tumors were studied by microdissection and microsatellite analysis of extracted DNA to assess the degree of microsatellite instability, a marker of defective mismatch repair, and to determine the extent and timing of allelic loss of two DNA mismatch repair genes, human Mut S homologue-2 (hMSH2) and human Mut L homologue-1 (hMLH1), and the tumor suppressor genes adenomatous polyposis coli gene (APC), p53, and DPC4. Microsatellite instability was detected in 16 of the tumors (34.8%). Loss of heterozygosity at microsatellites linked to the DNA mismatch repair genes, hMSH2 and/or hMLH1, was found in 9 cases (19.6%), usually in association with microsatellite instability. Importantly, the pattern of allelic loss was uniform in 8 of these 9 tumors, suggesting that clonal loss had occurred. Moreover, loss at these loci also occurred in nonmalignant tissue adjacent to 4 of these tumors, where it was associated with marked allelic heterogeneity. There was relatively infrequent loss of APC, p53, or DPC4 loci that appeared unrelated to loss of hMSH2 or hMLH1 gene loci. Loss of heterozygosity at hMSH2 and/or hMLH1 gene loci, and the associated microsatellite instability in premalignant hepatic tissues suggests a possible causal role in hepatic carcinogenesis in a subset of hepatomas. (HEPATOLOGY 1998;28:90-97.)

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Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families.

Abstract: A susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC)

Cited by 74 publications

References 20 publications

Linkage disequilibrium in the 13q12 region in Finnish late onset Alzheimer's disease patients

Linkage disequilibrium in the 13q12 region in Finnish late onset Alzheimer's disease patients

Haplotype associations define target regions for susceptibility loci in systemic lupus erythematosus

Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis

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