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H Kuivaniemi

Publications and source records attributed to H Kuivaniemi.

At least 19 recordsLinked to original sources
PubMed2003

[Schnyder's crystalline corneal dystrophy. Further narrowing of the linkage interval at chromosome 1p34.1-p36?].

BACKGROUND: Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease and can occur in association with hyperlipoproteinemia. The disease has been mapped to chromosome 1p34.1-p36. CASE REPORT: We report on a 66-year-old woman and her son with Schnyder's crystalline corneal dystrophy. The mother had type IV hyperlipoproteinemia and hypercholesterolemia while her son had hypercholesterolemia with elevated LDL-cholesterol. Analysis of microsatellite markers within the candidate interval of 1p34.1-p36 showed that the affected son and his unaffected brother had inherited different alleles only for the proximal marker D1S228 from their affected mother. CONCLUSIONS: The haplotype analysis suggests that either recombination has occurred, which would allow the candidate interval to be narrowed down, or alternatively, the SCCD in the reported family is not linked to chromosome 1, which would be a first indication of genetic heterogeneity in this disease. To reduce the risk of cardiovascular disease, hyperlipidemia should always be excluded in patients with Schnyder's crystalline corneal dystrophy.

Adult↗
PubMed2001

Genomic organization of the human COL3A1 and COL5A2 genes: COL5A2 has evolved differently than the other minor fibrillar collagen genes.

We report here on the complete structure of the human COL3A1 and COL5A2 genes. Collagens III and V, together with collagens I, II and XI make up the group of fibrillar collagens, all of which share a similar structure and function; however, despite the similar size of the major triple-helical domain, the number of exons coding for the domain differs between the genes for the major fibrillar collagens characterized so far (I, II, and III) and the minor ones (V and XI). The main triple-helical domain being encoded by 49-50 exons, including the junction exons, in the COL5A1, COL11A1 and COL11A2 genes, but by 43-44 exons in the genes for the major fibrillar collagens. Characterization of the genomic structure of the COL3A1 gene confirmed its association with the major fibrillar collagen genes, but surprisingly, the genomic organization of the COL5A2 gene was found to be similar to that of the COL3A1 gene. We also confirmed that the two genes are located in tail-to-tail orientation with an intergenic distance of approximately 22 kb. Phylogenetic analysis suggested that they have evolved from a common ancestor gene. Analysis of the genomic sequences identified a novel single nucleotide polymorphism and a novel dinucleotide repeat. These polymorphisms should be useful for linkage analysis of the Ehlers-Danlos syndrome and related disorders.

Animals↗
PubMed2001

Web-site-based recruitment for research studies on abdominal aortic and intracranial aneurysms.

Our current understanding on the pathogenesis of abdominal aortic and intracranial aneurysms is limited, but genetic and environmental factors as well as their interactions are likely to play important roles in the development and rupture of aneurysms. To identify genetic factors contributing to these diseases, we are carrying out genome-wide screening studies, which require a large number of patients and family members. Current methods of finding patients who qualify for genetic studies are, however, often costly and ineffective. To improve patient recruitment, a Web site was developed (cmmg.biosci.wayne.edu/ags). The site gives general information about our study, solicits participation into the study, and provides links to relevant medical and educational sites. During the time period of July, 1999, to December, 2000, the site received 5, 108 visits (13 visits/day). Approximately 20 research study applications are received each month. A total of 49% (57/117) of the individuals responding to the aortic aneurysm and 63% (84/134) responding to the intracranial aneurysm study report at least two affected blood relatives in the family and, therefore, qualify for our genetic studies. In conclusion, Web-based patient recruitment is successful and provides an improved success rate due to the fact that the responders are more motivated to participate in research studies.

Aortic Aneurysm, Abdominal↗
PubMed2001

A study of novel polymorphisms in the upstream region of vasoactive intestinal peptide receptor type 2 gene in autism.

We investigated the vasoactive intestinal peptide receptor type 2 (VIPR2) gene as a candidate gene for autism. We searched for mutations in the VIPR2 gene in autistic individuals, and 10 novel polymorphisms were identified. Three polymorphisms in the upstream region were studied in detail, and there was no significant difference in the frequencies between the autistic group (n = 14) and unrelated controls (n = 52). The distribution of the genotypes in two of the three polymorphisms differed somewhat between autistic subjects with gastrointestinal problems and those without. Moreover, there was a trend showing a correlation between the genotypes for the third polymorphism and the severity of stereotypical behavior as ranked by the Gilliam Autism Rating Scale. These preliminary results suggest that VIPR2 may have a role in gastrointestinal symptoms and stereotypical behaviors in autism, although a larger collection of samples suitable for transmission disequilibrium tests is necessary to validate the results.

Autistic Disorder↗
PubMed1999

Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms.

MMP3, MMP9, and PAI-1 are present at increased levels in abdominal aortic aneurysms (AAAs). The promoters of these genes contain polymorphisms, with alleles that exhibit different transcriptional activities in vitro. Association studies were performed using these polymorphisms and DNA isolated from 47 AAA patients, 57 intracranial aneurysm (IA) patients, and 174 controls, all from Finland. PAI-1 and MMP9 genotypes did not associate with aneurysms. The frequency of the 5A MMP3 allele was somewhat higher in the AAA than that in the control group (P = 0.0609 after Bonferroni correction), whereas the MMP3 allele frequencies in the IA group did not differ from those of the controls (P = 0.9667). These findings suggest that the transcriptionally more active 5A MMP3 allele might be a genetic risk factor for AAA among Finns. They are in agreement with previous studies demonstrating higher level of MMP3 expression in AAA than in control tissues.

Adult↗
PubMed1999

Founder mutations and the high prevalence of myotonia congenita in northern Finland.

OBJECTIVE AND BACKGROUND: To find an explanation at the molecular level for the high prevalence of myotonia congenita in northern Finland and the exceptional pattern of inheritance of the disease in many families, and to study genotype-phenotype correlation in the patients. METHODS: Forty-six patients with myotonia congenita and 16 unaffected relatives from 24 families were studied. All 23 exons and their flanking regions of the gene for the chloride channel protein (ClC-1) were sequenced from at least one patient from all families. RESULTS: There were three different mutations of ClC-1 in the patients: one in exon 11, a T-to-G transversion that resulted in the substitution of cysteine for phenylalanine at amino acid position 413 (F413C); one in exon 15, a C-to-T transition that resulted in the substitution of valine for alanine at amino acid position 531 (A531V); and one in exon 23, a C-to-T transition that resulted in the substitution of a stop codon for an arginine codon at amino acid position 894 (R894X). CONCLUSIONS: Molecular studies showed that even in families with apparent dominant inheritance, the actual mode of inheritance was autosomal recessive. This was explained not only by the observed consanguinity in some families but by an enrichment of three different mutations of the ClC-1 gene and a consequent high number of compound heterozygotes in the population. One of the mutations is unique to northern Finland. The conspicuous enrichment of the mutations is likely due to the founder effect and isolation by distance, as in other diseases in the Finnish heritage.

Adolescent↗
PubMed1999

Analysis of coding sequences for tissue inhibitor of metalloproteinases 1 (TIMP1) and 2 (TIMP2) in patients with aneurysms.

Aneurysms are characterized by dilation, i.e. expansion and thinning of all the arterial wall layers, which is accompanied by remodeling of the connective tissue. Genes involved in the regulation of tissue remodeling are therefore candidate genes. We analyzed TIMP1 and TIMP2 coding sequences in 12 individuals with abdominal aortic aneurysms (AAA), one individual with AAA and intracranial aneurysms (IA), four individuals with IA and two clinically unaffected individuals. We identified two nucleotide variants in both the TIMP1 and the TIMP2 coding sequences. All differences occurred in the third base positions of codons and were neutral polymorphisms. A significant difference was observed in the frequency of TIMP2 nt 573 polymorphism between 168 alleles from AAA patients and 102 control alleles.

Alleles↗
PubMed1997

Familial intracranial aneurysms.

BACKGROUND: We set out to determine the prevalence of incidental intracranial aneurysms in first-degree relatives aged 30 years or more of people with intracranial aneurysms, and to see if polycystic kidney disease contributes to the aggregation of familial intracranial aneurysms. METHODS: 91 families with two or more affected members had previously been identified from a 14 year series of 1150 intracranial aneurysm patients treated at the University Hospital of Kuopio, Finland. Magnetic resonance angiography was used as a preliminary screening method, followed by conventional four-vessel angiography to verify suspected aneurysms. Participants were also screened for polycystic kidneys by ultrasonography. FINDINGS: Incidental aneurysms were detected in 40 individuals: 38 of 438 individuals from 85 families without polycystic kidney disease or other diagnosed heritable disorders, and two of 22 individuals from six families known to have polycystic kidney disease. The crude and age-adjusted prevalence of incidental intracranial aneurysms among screened first-degree relatives was 8.7 (SE 1.3)% (95% CI 6.2-11.7) and 9.1 (1.4)% (6.2-11.7), respectively, for the familial group and the crude prevalence for the polycystic kidney group was 9.1 (6.1)% (1.1-29.2). INTERPRETATION: Our results demonstrate a high prevalence of incidental intracranial aneurysms among first-degree relatives aged 30 years or older of patients with the condition and indicate that the risk of having an aneurysm is about four times higher for a close relative than for someone from the general population. Also, polycystic kidney disease families are a small fraction of the familial intracranial aneurysm families.

Adult↗
PubMed1997

Two new recurrent nucleotide mutations in the COL1A1 gene in four patients with osteogenesis imperfecta: about one-fifth are recurrent.

Previous observations on mutations causing osteogenesis imperfecta (OI) suggested that unrelated patients had private mutations. Here preliminary studies on two patients with type I OI indicated that some mutations in the COL1A1 gene for type I procollagen cannot be detected by analyses of cDNAs. Therefore, we developed a protocol whereby 43 exon and exon flanking sequences of the COL1A1 gene can be amplified by PCR and scanned for mutations by denaturing gradient gel electrophoresis. Two new recurrent nucleotide mutations in the gene were found in four apparently unrelated patients with OI. Analysis of previous publications indicated that up to one-fifth of the mutations causing OI are recurrent in the sense that they were identical in apparently unrelated probands. About 80% of these identical mutations were in CpG dinucleotide sequences.

Alleles↗
PubMed1997

Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels.

This review summarizes the data on 278 different mutations found to date in the genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. A majority (217 mutations; 78% of the total) of the mutations are single-base and either change the codon of a critical amino acid (63%), or lead to abnormal RNA splicing (13%). Most of the amino acid substitutions are those of a bulkier amino acid for the obligatory glycine of the repeating-Gly-X-Y-sequence of the collagen triple helix (155; 56%). Altogether, 26 different mutations (9.4% of the mutations) occur in more than one unrelated individual. The 65 patients in whom the 26 mutations were characterized constitute almost one-fifth (20.5%) of the 317 patients analyzed. The mutations in types I, II, III, IX, X, and XI collagens cause a wide spectrum of diseases of bone, cartilage, and blood vessels, including osteogenesis imperfecta, a variety of chondrodysplasias, types IV and VII of the Ehlers-Danlos syndrome, and, rarely, some forms of osteoporosis, osteoarthritis, and familial aneurysms.

Animals↗
PubMed1997

Synthesis and conformational properties of a recombinant C-propeptide of human type III procollagen.

A cDNA was prepared that coded for the signal peptide of type III procollagen linked to the complete C-propeptide of the protein. The cDNA was then used to express the protein in a baculovirus recombinant system. Recombinant protein was recovered as a trimer from the medium of transfected cells in a yield of 1 to 2.5 mg per liter. Mapping of peptide fragments with and without reduction indicated that the protein contained the expected interchain disulfide bonds. Analysis by circular dichroism suggested that the conformation of the protein corresponded to the native conformation. Therefore, the protein should be appropriate for further tests of its biological function and analysis of structure by X-ray diffraction.

Animals↗
PubMed1997

A recombinant homotrimer of type I procollagen that lacks the central two D-periods. The thermal stability of the triple helix is decreased by 2 to 4 degrees C.

A D-period cassette system was developed that can be used to synthesize a variety of recombinant homotrimers of type I procollagen. A construct lacking the central two D-periods of pro alpha 1(I) chains was assembled and expressed as a recombinant protein in the mammalian cell line. The recombinant protein was purified to homogeneity and the thermal stability of the triple helix assayed by rapid protease digestion. The results indicated that deletion of the central 468 amino acids from the major triple helix lowered the thermal stability of the protein by 2 to 4 degrees C. The results therefore begin to define regions of the molecule that vary in their contributions to helical stability.

Bone Morphogenetic Protein 1↗
PubMed1996

Multiple defects in type III collagen synthesis are associated with the pathogenesis of abdominal aortic aneurysms.

Confluent skin fibroblast cultures were prepared from 40 patients diagnosed with and surgically treated for an abdominal aortic aneurysm. An analysis of secreted type I and type III collagen in the media of these fibroblast preparations revealed reduced secretion of type III collagen from six patients. DNA sequence analysis of the entire coding domain of the pro alpha 1 (III) collagen mRNA in skin fibroblast RNA from these six patients revealed a C to T substitution at nucleotide 607 in one of the probands that would result in the replacement of a leucine residue with phenylalanine in the second position of the first tripeptide repeat in the triple-helical domain of type III collagen. Allele-specific hybridization analysis of genomic DNA from this proband and family members indicated that this non-glycine substitution probably contributed to the aneurysmal phenotype in this patient. No coding sequence mutations were found in the other five patients. It is clear from this study, therefore, that aberrant synthesis of type III collagen, as a consequence of both a coding sequence mutation and other factors contributing to reduced secretion of type III procollagen, will result in the development of an aortic aneurysm in a significant percentage of patients with this disease.

Age of Onset↗
PubMed1996

Expression of mRNAs for lysyl oxidase and type III procollagen in cultured fibroblasts from patients with the Menkes and occipital horn syndromes as determined by quantitative polymerase chain reaction.

The Menkes syndrome and the occipital horn syndrome are two X-linked recessively inherited disorders characterized by abnormalities in copper metabolism. These abnormalities are associated with a reduction in the activity of lysyl oxidase (EC 1.4.3.13), an extracellular copper enzyme that initiates the crosslinking of collagens and elastin. We report here that the amount of lysyl oxidase mRNA, as studied by Northern blotting, and the number of lysyl oxidase mRNA molecules per picogram of RNA, as determined by a quantitative PCR method, were decreased in three cultured skin fibroblast lines from patients with the Menkes syndrome and two from patients with the occipital horn syndrome compared with four control cell lines. The decreased lysyl oxidase activity found in these disorders thus appears to be a least in part due to a pretranslational mechanism. No decrease was found in the number of the beta-actin mRNA molecules in the Menkes cell lines, but rather a slight increase, whereas a decrease was found in these molecules in the occipital horn cell lines. An additional abnormality found in the Menkes cell lines was a significant increase in the number of mRNA molecules for type III procollagen in two of the three cell lines investigated. The present and previous data indicate that the Menkes syndrome may involve several abnormalities in the expression of genes for connective tissue proteins.

Base Sequence↗
PubMed1996

Substitution of arginine for glycine at position 154 of the alpha 1 chain of type I collagen in a variant of osteogenesis imperfecta: comparison to previous cases with the same mutation.

A substitution of arginine for glycine at amino acid position 154 of the alpha 1(I) collagen chain was found in a father and his three children. The phenotype of the patients includes manifestations of types I and III/IV osteogenesis imperfecta, but appears to be milder than that of the previously described two unrelated patients that had the identical mutation in the alpha 1(I) collagen chain. The variability in the phenotype raises the possibility of epistatic loci or environmental effects on expression of the disorder.

Adult↗