PubMed Health⌕ Search

Biomedical subjects

K Kainulainen

Publications and source records attributed to K Kainulainen.

10 recordsLinked to original sources
PubMed1992

Elucidation of the gene defect in Marfan syndrome. Success by two complementary research strategies.

Marfan syndrome, which is characterized by manifestations in the skeletal, ocular and cardiovascular systems, is one of the most common inherited connective-tissue disorders. The independently performed genetic assignment of the Marfan locus and classical biochemical and immunohistochemical analyses complemented each other in the search for the Marfan gene defect and in 1991 the fibrillin gene in chromosome 15 was identified as the Marfan gene. So far, three mutations leading to the Marfan phenotype have been reported in this gene coding for a microfibrillar protein. The available data suggests a wide spectrum of different mutations of fibrillin and although mutations of the fibrillin gene account for the majority of Marfan cases, evidence also exists for locus heterogeneity in a minority of Marfan cases.

Genetic Linkage↗
PubMed1992

Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides.

Biochemical and molecular genetic studies have recently suggested that mutations in the gene coding for fibrillin on chromosome 15 result in Marfan syndrome. To our knowledge, only one mutation in the fibrillin gene has been published. Here we report the results of screening 20 unrelated MFS patients for mutations in fibrillin cDNA by the single-strand conformation polymorphism technique. We found two mutations, both of which appear in the heterozygote form and code for a shortened fibrillin polypeptide. The first mutation is a large in-frame deletion of 366 bases of the fibrillin mRNA, shown to result in a truncated but secreted polypeptide found in the fibroblast culture of the patient. The second mutation is a G-to-A transition resulting in the substitution of a stop codon for a tryptophan codon and thus predicting the premature termination of the polypeptide chain. We screened 60 other, unrelated MFS patients for these mutations as well as for the previously reported mutation (arginine-239 to proline) and found none of the three mutations in any of these patients. These data suggest that most MFS families carry their own distinct mutation.

Base Sequence↗
PubMed1991

Marfan syndrome: no evidence for heterogeneity in different populations, and more precise mapping of the gene.

Marfan syndrome is a dominantly inherited connective tissue disorder with manifestations in the cardiovascular, ocular, and skeletal systems. The diagnosis is hampered by both high variability in the phenotypic expression and late manifestation of symptoms. The cause of Marfan syndrome remains unknown, but our group has recently reported the genetic linkage of Marfan syndrome to a polymorphic marker on chromosome 15. To analyze the possible heterogeneity behind Marfan syndrome, we have performed linkage analyses for four chromosome 15 markers in 17 families from five different populations: Scottish, English, Swiss, American, and Finnish. By combining the linkage data of all the studied families into a LINKMAP analysis we obtained a maximal LOD score of 11.2, which maps the Marfan syndrome locus between D15S25 and D15S45 on the long arm of chromosome 15. The data reveal no evidence for genetic heterogeneity behind Marfan syndrome and provide us with a more precise location of both the Marfan syndrome locus and flanking markers. This information will provide the basis for the DNA diagnostics of Marfan syndrome in the future.

Chromosome Mapping↗
PubMed1990

Progestin induction of 17 beta-hydroxysteroid dehydrogenase enzyme protein in the T-47D human breast-cancer cell line.

Steroid regulation of 17 beta-hydroxysteroid dehydrogenase (17-HSD) was studied in the T-47D human breast-cancer cell line, using a radioimmunoassay. In addition, 3 mRNA species (2.4, 1.4, and 0.9 kb) specific for the enzyme were shown to be present in these cells. All the synthetic progestins tested (ORG 2058, R5020, medroxyprogesterone acetate) significantly increased the immunoreactive enzyme protein concentration, while other types of steroids, such as testosterone, oestradiol and dexamethasone, were ineffective. The progestin-specific induction of 17-HSD was dose-related and was maximum in about 5 days. An antiprogestin, RU 486, when used in combination with synthetic progestins, blocked the progestin-induced increase of 17-HSD concentration very effectively. A good correlation was observed in the different experiments between the enzyme activity and the immunoreactive 17-HSD concentration. We conclude that progestins induce 17-HSD in T-47D cells and that the induction occurs via an increased accumulation of enzyme protein.

Breast Neoplasms↗
PubMed1990

Deficient expression of the gene coding for decorin in a lethal form of Marfan syndrome.

The markedly decreased level of the messenger RNA of decorin, an abundant dermatan/chondroitin sulfate proteoglycan was found in the skin fibroblast culture of a lethally sick Marfan infant. Also, the amount of decorin polypeptide in the culture medium of the fibroblasts of this infant was markedly decreased. When the effect of interleukin-1 beta on the transcription of decorin was tested in these fibroblasts, the response was deficient as compared to control fibroblasts whereas transcription of type I and III collagen genes and versican was stimulated normally. The decreased decorin mRNA level, unresponsive to interleukin-1 beta in this lethally sick Marfan patient, stresses the significance of this proteoglycan in the formation of normal connective tissue. Furthermore, the low expression of this gene could be responsible for the connective tissue findings in this patient, representing a rare type of Marfan syndrome. The identical finding in three other, unrelated Marfan individuals suggests a more general significance of deficient decorin expression in this disease.

Blotting, Western↗
PubMed1990

Location on chromosome 15 of the gene defect causing Marfan syndrome.

BACKGROUND: Marfan syndrome, "the founding member" of the heritable disorders of connective tissue, is a common autosomal dominant disorder with highly variable clinical manifestations in the skeletal, ocular, and cardiovascular systems. The fundamental defect leading to this disease has escaped definition despite decades of research efforts by several groups of investigators. METHODS AND RESULTS: Using linkage analyses with polymorphic markers of the human genome, we mapped the genetic defect to chromosome 15 in five families with Marfan syndrome. With three polymorphic markers we obtained definitive proof of linkage in these families (lod score = 3.92, theta = 0.0 +/- 0.11). The most probable location of the gene for the disease is currently D15S45 (lod score = 3.32, theta = 0.0 +/- 0.12). CONCLUSIONS: The chromosomal localization of the mutation in Marfan syndrome is a first step toward the isolation and characterization of the defective gene and serves as a diagnostic test in families in which cosegregation of these markers with the disease has been confirmed.

Chromosome Mapping↗
PubMed1990

Marfan syndrome: exclusion of genetic linkage to five genes coding for connective tissue components in the long arm of chromosome 2.

Marfan syndrome represents a heterogeneous connective tissue disease, the symptoms arising in several tissues and organs. The defective gene(s) behind this autosomal dominant condition has not been found despite considerable research. The main targets of the research have been the genes coding for connective tissue components. Several of the candidate genes suspected to be defective in Marfan syndrome are located on the long arm of chromosome 2. These genes include a cluster of two genes coding for fibrillar collagens COL3A1 and COL5A2, and a third member of the collagen gene family: COL6A3. Furthermore, genes for elastin (ELN) and fibronectin (FN) are also located in this area of chromosome 2. We studied this chromosomal area using restriction fragment length polymorphism (RFLP) linkage analysis in five Finnish Marfan families with affected members in three generations. In two point linkage analyses, Lod scores of -3.192 (theta = 0.1) to COL3A1, -1.683 (theta = 0) to COL6A3 and -2.664 (theta = 0.01) to FN were obtained, whereas the linkage analysis between elastin and the disease was non-informative (Lod score 0.444, theta = 0). With the multipoint linkage analysis that permits simultaneous examination of several loci and more efficient use of family data, we obtained an exclusion of all these loci as the site of the mutation leading to Marfan syndrome in these families.

Chromosomes, Human, Pair 2↗