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P Sistonen

Publications and source records attributed to P Sistonen.

At least 37 records · Page 2Linked to original sources
PubMed1999

CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family-based association study.

Celiac disease (CD) is a common small intestinal injury caused by sensitivity to gliadin in genetically-predisposed individuals. The only susceptibility locus established is the HLA-DQ. We tested whether the chromosomal region of the CD28/CTLA4 genes on 2q33 is linked to CD. These genes encode receptors regulating the T-lymphocyte activation. Recently, this gene region was reported to be linked to the susceptibility to many autoimmune diseases, including insulin-dependent diabetes (IDDM12locus). It is thus an obvious candidate locus also for CD, since the intestinal injury is mediated by the immune system. Genetic linkage between seven marker loci in this gene region and CD was studied in 69 Finnish families. In the multipoint linkage analysis, the highest non-pararametric linkage score (NPL) was 1.75 (P=0.04) for D2S116, suggesting weak linkage for this candidate locus. To evaluate this finding, an additional 31 families were typed for all markers. In the combined set of 100 families the NPL score for marker D2S116 was 2.55 (P=0.006) and for other markers 1.90-2.47 (P=0.029-0.007), supporting genuine linkage at this region. Significantly, locus D2S116 also showed a clear allelic association in these 100 families (P=0.0001). The transmission/disequilibrium test (TDT) for locus D2S116 gave preliminary evidence for preferential maternal non-transmission of allele *136 to patients (TDTmax=8.3; P<0.05). No paternal deviation was found suggesting that the effect of the locus might be mediated by a sex-dependent factor protective against CD. Our results indicate that the CD28/CTLA4 gene region can contain a novel susceptibility locus for CD and support the hypothesis that CD has an immune system-mediated component. Like the HLA, the CD28/CTLA4 genes appear to be associated with genetic susceptibility to various autoimmune diseases.

Abatacept↗
PubMed1999

Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer.

Germline mutations in LKB1 have been reported to underlie familial Peutz-Jeghers syndrome (PJS) with intestinal hamartomatous polyps and an elevated risk of various neoplasms. To investigate the prevalence of LKB1 germline mutations in PJS more generally, we studied samples from 33 unrelated PJS patients including eight non-familial sporadic patients, 20 familial patients and five patients with unknown family history. Nineteen germline mutations were identified, 12 (60%) in familial and four (50%) in sporadic cases. LKB1 mutations were not detected in 14 (42%) patients, indicating that the existence of additional minor PJS loci cannot be excluded. LKB1 is predicted to encode a serine/threonine kinase. To demonstrate the putative Lkb1 kinase function and to study the consequences of LKB1 mutations in PJS and sporadic tumors, we have analyzed the kinase activity of wild-type and mutant Lkb1 proteins. Interestingly, while most of the small deletions or missense mutations resulted in loss-of-function alleles, one missense mutation (G163D) previously identified in a sporadic testicular tumor demonstrated severely impaired but detectable kinase activity.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

The LWb blood group as a marker of prehistoric Baltic migrations and admixture.

Archaeological findings and historical records indicate frequent migrations and exchange of genetic material between populations in the Baltic Sea area. However, there have so far been very few attempts to trace migrations in this area using genetic markers. We have studied the Baltic populations with respect to exceptional variations in the frequencies of the Landsteiner-Wiener (LW) blood group. The frequency of the uncommon LWb gene was high in the Balts, around 6% among Latvians and Lithuanians, very low among the other western Europeans (0-0.1%) and apparently absent in Asiatic and African populations. From the Baltic region of peak frequency there was a regular decline of LWb incidence (a descending cline) in the neighboring populations: 4.0% in the Estonians, 2.9% in the Finns, 2. 2% in the Vologda Russians, and 2.0% in the Poles. Thus the distribution of LWb suggests considerable and extensive Baltic admixture, especially in the north and northeast direction. In Southern Sweden with an LWb frequency of 0.3%, the Baltic influence appeared slight, while in the population of the Swedish island Gotland in the middle of the Baltic Sea there was a significantly increased LWb frequency of 1.0% compared with that of Western European countries. The distinction of codominantly inherited LW antigenic forms, LWa and LWb (previously Nea), is known to be due to a single base substitution. Based on our population data, it is plausible that the expansion of this point mutation occurred only once during human history. Furthermore, our data indicate that the expansion of the LWb mutation occurred in Balts and that LWb can be considered a 'Baltic tribal marker', its presence in other populations being an indicator of the degree of Baltic genetic influence.

Alleles↗
PubMed1998

Mutations in the SMAD4/DPC4 gene in juvenile polyposis.

Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.

Cell Membrane↗
PubMed1998

A novel splice site mutation of the EXT2 gene in a Finnish hereditary multiple exostoses family. Mutations in brief no. 197. Online.

Hereditary multiple exostoses is a dominantly inherited disease characterized by multiple benign osteochondromas. The affected individuals have an increased risk of developing sarcoma. A large Finnish family with hereditary multiple exostosis was analyzed to find the disease-causing mutation. Blood samples were obtained from 35 family members, including 21 affected and 14 unaffected individuals. Using 2-point linkage analysis the EXT phenotype was shown to be linked to the recently cloned EXT2 gene on chromosome 11p11. The coding region of the gene was sequenced and a previously unreported splice site mutation found. This G to T transversion within a 5-prime splice donor site following exon 6 was shown to cause aberrant splicing of RNA. The described change is considered to be a novel disease-causing mutation in the EXT2 gene.

Alternative Splicing↗
PubMed1998

Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS: The phenotype of hereditary nonpolyposis colorectal cancer shows interfamilial and intrafamilial variation even in the presence of identical predisposing mutations, suggesting the existence of additional phenotype determinants. The modifying role of genetic polymorphisms in loci involved in carcinogen metabolism was studied. METHODS: We focused on colon cancers from kindreds sharing one of two predisposing mutations (mutation 1 or 2) in the mismatch repair gene MLH1 (78 and 14 tumors, respectively). Polymorphisms in N-acetyltransferase 1 (NAT1) and glutathione S-transferase (GST) M1 and GSTT1 were investigated. RESULTS: The NAT1 allele 10 was associated with lower median age at diagnosis in both groups. In mutation 1 group, the NAT1 allele 10 was a risk factor for distal tumor location, both alone (P = 0.028) and combined with the GSTT1-positive genotype (P = 0.008). On the other hand, the combined null genotype of GSTM1 and GSTT1 was associated with proximal tumors. Associations with tumor location were not observed in patients with mutation 2, probably reflecting a small sample size. CONCLUSIONS: The results suggest that genetic polymorphisms in carcinogen metabolism modify the age of onset and tumor location in individuals with inherited deficiency of DNA mismatch repair.

Adult↗
PubMed1997

Exclusion of PTEN and 10q22-24 as the susceptibility locus for juvenile polyposis syndrome.

Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22-24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. Lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22-24.

Chromosomes, Human, Pair 10↗
PubMed1997

Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis.

Many human cancer susceptibility genes have been successfully mapped by genetic linkage studies. One that has so far eluded researchers is that for Peutz-Jeghers (P-J) syndrome, a condition characterized by intestinal hamartomatous polyposis and melanin spots of the lips, buccal mucosa and digits. A dramatically elevated risk of malignancy has also been documented. Gastrointestinal tumours as well as cancers of the breast, ovary, testis and uterine cervix appear to be overrepresented in families with this syndrome. The nature of hamartomatous polyps is equivicol. Hamartomas are usually considered histologically benign, but in the case of Peutz-Jeghers patients, there are reports of adenomatous and malignant changes in the polyps, and the possibility of a hamartoma-carcinoma sequence has been discussed. A search for a putative tumour suppressor locus was made using comparative genomic hybridization (CGH) of Peutz-Jeghers polyps, combined with loss of heterozygosity (LOH) study. Genetic linkage analysis in 12 families using markers from a deletion site demonstrated the presence of a high-penetrance locus in distal 19p with a multipoint lod score of 7.00 at marker D19S886 without evidence of genetic heterogeneity. The study demonstrates the power of CGH combined with LOH analysis in identifying putative tumour suppressor loci, and provides molecular evidence of malignant potential in hamartomas.

Adenocarcinoma↗
PubMed1997

Lysinuric protein intolerance (LPI) gene maps to the long arm of chromosome 14.

Lysinuric protein intolerance (LPI) is an autosomal recessive disease characterized by defective transport of cationic amino acids and by hyperammonemia. Linkage analysis in 20 Finnish LPI families assigned the LPI gene locus to the proximal long arm of chromosome 14. Recombinations placed the locus between framework markers D14S72 and MYH7, a 10-cM interval in which the markers D14S742, D14S50, D14S283, and TCRA showed no recombinations with the phenotype. The phenotype was in highly significant linkage disequilibrium with markers D14S50, D14S283, and TCRA. The strongest allelic association obtained with marker TCRA, resulting in a P(excess) value of .98, suggests that the LPI gene locus lies in close proximity to this marker, probably within a distance of < 100 kb.

Adult↗
PubMed1997

Assignment of the mulibrey nanism gene to 17q by linkage and linkage-disequilibrium analysis.

Mulibrey nanism (MUL) is an autosomal recessive disorder with unknown basic metabolic defect. It is characterized by growth failure of prenatal onset, characteristic dysmorphic features, constrictive pericardium, hepatomegaly as a consequence of constrictive pericardium, yellowish dots in the ocular fundi, and J-shaped sella turcica. Hypoplasia of various endocrine glands, causing hormone deficiencies, is common. Here we report the assignment of the MUL gene, by linkage analysis in Finnish families, to a 7-cM region flanked by D17S1799 and D17S948 on chromosome 17q. Multipoint linkage analysis gave a maximum LOD score of 5.01 at loci D17S1606-D17S1853 and at D17S1604. The estimate of the critical MUL region was further narrowed to within approximately 250 kb of marker D17S1853 by linkage disequilibrium analysis. Positional candidate genes that belong to the growth hormone and homeobox B gene clusters were excluded. These data confirm the autosomal recessive inheritance of MUL and allow highly focused attempts to clone the gene.

Abnormalities, Multiple↗
PubMed1996

Refined mapping of the Usher syndrome type III locus on chromosome 3, exclusion of candidate genes, and identification of the putative mouse homologous region.

A locus for Usher syndrome type III (USH3; MIM No. 276902) was recently assigned to a 5-cM region on chromosome 3q. We constructed a yeast artificial chromosome contig that allowed us to position novel polymorphisms in the region. These were typed in a total of 32 pedigrees from a geographically isolated Finnish founder population in which a putative single ancestral USH3 mutation segregates. A multipoint linkage analysis assigned USH3 to a 4-cM region between D3S1555 and a novel marker D3S3625. By analysis of linkage disequilibrium and historical recombinations in 77 USH3 chromosomes, the location of the Finnish USH3 mutation could be narrowed to an approximately 1-cM interval between the markers D3S1299 and D3S3625. A gene for profilin-2 (PFN2) was mapped in the vicinity and excluded as a candidate for USH3 by sequencing. The putative mouse homolog of PFN2 was mapped to mouse chromosome 3, thus suggesting a localization for the mouse homolog of USH3.

Alleles↗
PubMed1996

Point mutations characterize KEL10, the KEL3, KEL4, and KEL21 alleles, and the KEL17 and KEL11 alleles.

BACKGROUND: The Kell blood group system is complex, consisting of five sets of alleles and expressing high- and low-incidence antigens and at least 11 other independently expressed antigens. The molecular basis of two sets of alleles: KEL1 (K) and KEL2 (k) and KEL6 (Jsa) and KEL7 (Jsb) have been elucidated as single-base mutations leading to amino acid changes. The molecular basis for the KEL3 (Kpa), KEL4 (Kpb), and KEL21 (Kpc) alleles, the KEL11(Cote) and KEL17(Wka) alleles, and for KEL10 (UIa) is now reported. STUDY DESIGN AND METHODS: Genomic DNA from unrelated individuals with KEL:3,-4,-21 [Kp(a+b-c-)], KEL:-3,-4,21 [Kp(a-b-c+)], KEL:17,-11, and KEL:10 (UIa) phenotypes was amplified by polymerase chain reaction (PCR) with primers for the 19 exons of KEL. The PCR products were sequenced and compared to the DNA sequences of a common Kell system phenotype, KEL:-3,4,-21,-17,-10. Base mutations found were confirmed by restriction fragment length polymorphism analysis in which DNA of unrelated persons with similar red cell phenotypes was used. RESULTS: In all cases, single-base mutations were responsible for the expression of the various antigens. In KEL3 (Kpa), KEL4 (Kpb), and KEL21 (Kpc), point mutations at the same codon in exon 8, encoding amino acid residue 281, distinguish the three genes. KEL4 has the CGG codon for arginine, KEL3 has the TGG codon for tryptophan, and KEL21 has the CAG codon for glutamine. KEL17 has a T1025C mutation in exon 8, encoding a valine-to-alanine amino acid change at residue 302. KEL10 has an A1601T mutation in exon 13, encoding a glutamic acid-to-valine change at residue 494. In all cases, the point mutations created restriction enzyme sites, and PCR-based restriction fragment length polymorphisms confirmed that these point mutations occurred in unrelated persons with the same red cell phenotype. CONCLUSION: Single-base substitutions characterize the KEL3, KEL21, KEL17, and KEL10 genes. The allelic relationship of KEL3, KEL4, and KEL21 was confirmed because the mutations occur in the same codon, expressing different amino acids. PCR-based restriction fragment length polymorphisms can be used to distinguish genotypes.

Alanine↗
PubMed1996

Haplotype analysis in prenatal diagnosis and carrier identification of Salla disease.

Salla disease (SD) is an autosomal recessive disorder in which free sialic acid (N-acetyl neuraminic acid) accumulates in lysosomes. A specific transport mechanism for acidic monosaccharides on the lysosomal membrane has recently been described, but the molecular deficiency causing SD is still unknown. We have previously mapped the SD gene to 6q14-q15 by means of genetic linkage analysis and restricted the positive chromosomal area to less than 100 kb with linkage disequilibrium mapping. The two best allelic association markers have now retrospectively been used in five prenatal analyses originally studied with sialic acid assays in chorionic villus specimens. In four cases an unaffected fetus was predicted with a probability level of more than 94%, which was in concordance with the biochemical data. One fetus was predicted to be affected with over 96% probability, as was shown by free sialic acid assays in a CVS sample and in fetal tissues after termination of the pregnancy. Risk calculations incorporating disequilibrium were also used to predict the carrier status in members of six families with previous SD cases, and also in a few cases with no known family history of SD. DNA marker based analysis thus provides a reliable method for risk estimations in prenatal cases and for carrier identification of SD.

Adult↗
PubMed1996

Evidence that the low-incidence red cell antigens Rla and Lsa are identical.

Testing of Ls(a+) and Rl(a+) red cells with numerous antisera containing antibodies to low-incidence antigens indicated that these antigens are identical. This conclusion was confirmed by adsorption and elution tests, and supported by immunoblotting of Ls(a+) and Rl(a+) cells with antibodies to glycophorin C and glycophorin D.

Journal Article↗
PubMed1996

Progressive myoclonus epilepsy EPM1 locus maps to a 175-kb interval in distal 21q.

The EPM1 locus responsible for progressive myoclonus epilepsy of Unverricht-Lundborg type (MIM 254800) maps to a region in distal chromosome 21q where positional cloning has been hampered by the lack of physical and genetic mapping resolution. We here report the use of a recently constituted contig of cosmid, BAC, and P1 clones that allowed new polymorphic markers to be positioned. These were typed in 53 unrelated disease families from an isolated Finnish population in which a putative single ancestral EPM1 mutation has segregated for an estimated 100 generations. By thus exploiting historical recombinations in haplotype analysis, EPM1 could be assigned to the approximately 175-kb interval between the markers D21S2040 and D21S1259.

Adult↗
PubMed1996

The genetic relationship between the Finns and the Finnish Saami (Lapps): analysis of nuclear DNA and mtDNA.

The genetic relationships between two Finno-Ugric-speaking populations, the Finns and the Finnish Saami (Lapps), were studied by using PCR for six nuclear-DNA marker loci, mitochondrial restriction-site polymorphism, and sequence variation of a 360-bp segment of the mitochondrial control region. The allele frequencies of each of the nuclear-DNA marker loci and the frequencies of mtDNA restriction haplotypes were significantly different between the populations. The Saami showed exceptionally low variation in their mtDNA restriction sites. The 9-bp deletion common in East Asian populations was not observed, nor did the haplotype data fit into the haplogroup categorization of Torroni et al. The average number of nucleotide substitutions from the mtDNA haplotype data indicated that the Finnish Saami may be closer to the Finns than to the other reference populations, whereas nuclear DNA suggested that the Finns are more closely related to the European reference populations than to the Finnish Saami. The similarity of the Finns to the other Europeans was even more pronounced according to the sequence data. We were unable to distinguish between the Finns and either the Swiss or Sardinian reference populations, whereas the Finnish Saami clearly stood apart. The Finnish Saami are distinct from other Circumarctic populations, although two of the lineages found among the Saami showed closer relationship to the Circumarctic than to the European lineages. The sequence data indicated an exceptionally high divergence for the Saami mtDNA control lineages. The distribution of the pairwise nucleotide differences in the Saami suggested that this population has not experienced an expansion similar to what was indicated for the Finns and the reference populations.

Base Sequence↗
PubMed1996

Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer.

Two mutations in the DNA mismatch repair gene MLH1, referred to as mutations 1 and 2, are frequent among Finnish kindreds with hereditary nonpolyposis colorectal cancer (HNPCC). In order to assess the ages and origins of these mutations, we constructed a map of 15 microsatellite markers around MLH1 and used this information in haplotype analyses of 19 kindreds with mutation 1 and 6 kindreds with mutation 2. All kindreds with mutation 1 showed a single allele for the intragenic marker D3S1611 that was not observed on any unaffected chromosome. They also shared portions of a haplotype of 4-15 markers encompassing 2.0-19.0 cM around MLH1. All kindreds with mutation 2 shared another allele for D3S1611 and a conserved haplotype of 5-14 markers spanning 2.0-15.0 cM around MLH1. The degree of haplotype conservation was used to estimate the ages of these two mutations. While some recessive disease genes have been estimated to have existed and spread for as long as thousands of generations worldwide and hundreds of generations in the Finnish population, our analyses suggest that the spread of mutation 1 started 16-43 generations (400-1,075 years) ago and that of mutation 2 some 5-21 generations (125-525 years) ago. These datings are compatible with our genealogical results identifying a common ancestor born in the 16th and 18th century, respectively. Overall, our results indicate that all Finnish kindreds studied to date showing either mutation 1 or mutation 2 are due to single ancestral founding mutations relatively recent in origin in the population. Alternatively, the mutations arose elsewhere earlier and were introduced in Finland more recently.

Adult↗