Biomedical subjects

Leena Ala-Kokko

Publications and source records attributed to Leena Ala-Kokko.

28 records · Page 2Linked to original sources

PubMed2003

Mapping of a new autosomal recessive nonsyndromic hearing loss locus (DFNB32) to chromosome 1p13.3-22.1.

Approximately 80% of the hereditary hearing loss is nonsyndromic. Isolated deafness is the most genetically heterogeneous trait. We have ascertained 10 individuals from a large consanguineous Tunisian family with congenital profound autosomal recessive deafness. All affected individuals are otherwise healthy. Genotype analysis excluded linkage to known recessive deafness loci in this family. Following a genome wide screening, a linkage was detected only with locus D1S206 on chromosome 1, thereby defining a novel deafness locus, DFNB32. In order to confirm linkage and for fine mapping the genetic interval, 12 individuals belonging to this family were added and 19 microsatellite markers were tested. A maximum two-point lodscore of 4.96 was obtained at a new polymorphic marker D1S21401. Haplotype analysis defined a 16 Mb critical region between D1S2868 and afmb014zb9. The interval of DFNB32 locus overlap with DFNA37 locus and the Marshall and Stickler syndromes locus. The entire coding region of COL11A1, responsible of the later syndromes, was screened and no mutation was observed. Towards the identification of the DFNB32 gene, a search on the Human Cochlear cDNA Library and EST Database was done. The genes corresponding to the ESTs found in the DFNB32 interval are being screened for deafness-causing mutations.

Chromosome Mapping↗

PubMed2003

Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia.

Cleft palate is a common birth defect, but its etiopathogenesis is mostly unknown. Several studies have shown that cleft palate has a strong genetic component. Robin sequence consists of three of the following four findings: micrognathia, glossoptosis, obstructive apnea, and cleft palate. While cleft palate is mainly nonsyndromic, about 80 percent of Robin sequence cases are associated with syndromes. Mutations in genes coding for cartilage collagens II and XI, COL2A1, COL11A1 and COL11A2, have been shown to cause chondrodysplasias that are commonly associated with Robin sequence, micrognathia or cleft palate. We therefore analyzed a cohort of 24 patients with nonsyndromic Robin sequence, 17 with nonsyndromic cleft palate and 21 with nonsyndromic micrognathia for mutations in COL11A2. A total of 23 Robin sequence patients were also analyzed for mutations in COL2A1 and COL11A1. We detected two disease-associated mutations in patients with Robin sequence, an Arg to stop codon mutation in COL11A2 and a splicing mutation in COL11A1. Two putatively disease-associated sequence variations were found in COL11A1 in Robin sequence patients, one in COL11A2 in a patient with micrognathia and one in COL2A1 in two patients with Robin sequence. The results showed that sequence variations in these genes can play a role in the etiology of Robin sequence, cleft palate and micrognathia but are not common causes of these phenotypes.

Cleft Palate↗

PubMed2002

COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction.

STUDY DESIGN: Cross-sectional. OBJECTIVES: To evaluate the interaction between the COL9A3 gene polymorphism and persistent obesity in relation to lumbar disc degeneration. SUMMARY OF BACKGROUND DATA: Obesity has been suggested to be a risk factor for disc degeneration. There is some indication for an association between collagen IX genes and lumbar disc disease characterized by sciatica. However, the interaction between those factors in their influences on the risk of disc degeneration has not been studied. METHODS: Blood samples from 135 middle-aged men who had undergone magnetic resonance imaging (MRI) of the lumbar spine were analyzed for the presence of an arginine to tryptophan change in the COL9A3 gene (Trp3 allele). The men represented three occupations: 41 were machine drivers, 42 were carpenters, and 52 were office workers. The discs L2/L3-L5/S1 were evaluated on MRI, using decreased signal intensity of the nucleus pulposus, posterior disc bulges, and decreased disc height as signs of disc degeneration. Based on self-reports on body height and weight currently and at the age of 25 years, obesity history was classified as no obesity, persistent obesity, and other. Rothman's synergy index was used as a measure of interaction between two factors. RESULTS: The Trp3 allele and persistent obesity acted synergistically to increase the risk of dark nucleus pulposus, posterior disc bulge, and decreased disc height at L4/L5; of multilevel posterior disc bulges; and of decreased disc height. From 45% to 71% of disc degeneration among persistently obese individuals with the Trp3 allele could be attributed to the synergism of these two factors. CONCLUSION: The effect of obesity on lumbar disc degeneration seems to be modified by the collagen IX gene polymorphism, so that people who carry the Trp3 allele are at increased risk if they are persistently obese.

Alleles↗

PubMed2002

Down-regulation of human type II collagen gene expression by transforming growth factor-beta 1 (TGF-beta 1) in articular chondrocytes involves SP3/SP1 ratio.

Although transforming growth factor beta1 (TGF-beta1) is generally considered as a stimulator of type I collagen production in smooth organs, we found that it can inhibit type II collagen biosynthesis in primary rabbit articular chondrocytes (RAC) at transcriptional levels. Constructs of promoter and first intron sequences associated with the luciferase reporter gene were used to delineate the gene sequences involved in TGF-beta1 control of human COL2A1 gene transcription. Cotransfection of these DNA fragments with a TbetaRII/I cDNA hybrid receptor, capable of inducing a TGF-beta1 dominant negative effect, showed that TGF-beta1 inhibits specifically COL2A1 gene transcription in RAC by a 63-bp proximal promoter. Footprint and gel retardation analyses revealed that the TGF-beta1-induced inhibition effect exerted through the 63-bp promoter sequence implies a multimeric complex that binds to the -41/-33 sequence and involves Sp1 and Sp3 transcription factors. Transfection of decoy Sp-binding oligonucleotides corroborated the implication of the proximal promoter in the TGF-beta1-induced inhibition of COL2A1 gene transcription. In addition, TGF-beta1 was found to increase the expression of Sp3 without significant changes to its binding level, but repressed both the biosynthesis and binding activity of Sp1. In functional assays, Sp3 inhibited the 63-bp promoter activity and prevented Sp1 induction of transcription. These findings suggest that TGF-beta1 inhibition of COL2A1 gene transcription in RAC is mediated by an increase of the Sp3/Sp1 ratio and by the repression of Sp1 transactivating effects on that gene.

Animals↗

PubMed2002

Magnetic resonance imaging findings in relation to the COL9A2 tryptophan allele among patients with sciatica.

STUDY DESIGN: The phenotype of patients with sciatica who have the Trp2 allele is characterized cross-sectionally. OBJECTIVE: To determine whether it is possible to differentiate patients with the Trp2 allele clinically or by magnetic resonance imaging. SUMMARY OF BACKGROUND DATA: Several studies have indicated a positive family history for intervertebral disc disease. Previously, a dominantly inherited defect was identified in the COL9A2 gene that changed a codon for glutamine to that for tryptophan in the alpha2 chain of collagen IX (Trp2 allele). This change may render intervertebral discs more fragile. METHODS: Clinical findings, clinical symptoms, and magnetic resonance imaging (1.5-T) findings from 159 patients with sciatica were evaluated according to the presence of the Trp2 allele. Additionally, the magnetic resonance imaging scans of 22 family members from three families were evaluated. These scans were analyzed intervertebral disc and endplate degeneration, Schmorl's nodes, transverse tears (hyperintensity in the region of Sharpey's fibers), high-intensity zone lesions (bright spots in the dorsal anulus), and radial tears (hyperintense linear area from the nucleus to the outer part of the anulus on T2 sequences). RESULTS: Six patients with sciatica and 11 family members had the Trp2 allele. No homozygotes were found. Clinical symptoms of patients with and those without the Trp2 allele were similar. Patients with sciatica who had the Trp2 allele were significantly more flexible (P < 0.05), according to the modified Schober measure. The disc and endplate degeneration in 6 patients with the Trp2 allele and their 18 controls (matched for age, occupation, gender) without the allele did not differ significantly, whereas family members with the Trp2 allele had a greater degree of disc and endplate degeneration at L5-S1. The overall prevalence of endplate degeneration was high in this study. The prevalences of dorsal transverse tears, high-intensity zone lesions, and Schmorl's nodes did not differ among patients with sciatica or family members according to the presence of the Trp2 allele. There was, however, a trend for increased prevalence of radial tears in nonherniated discs among the Trp2 allele-positive subjects (3 of 6 patients with sciatica and 3 of 11 family members), as compared with the Trp2-negatives subjects (none of 18 "matched" patients or 11 family members). CONCLUSION: The patients with the Trp2 allele were more flexible, and more often tended to have a radial tear in a nonherniated disc than their control counterparts.

Adult↗

PubMed2002

Analysis of the COL3A1 gene in patients with spontaneous cervical artery dissections.

The etiology of spontaneous cervical artery dissection (sCAD) is unknown. An underlying connective tissue disorder has been suggested. As a collagen disease is conceivable several genes encoding fibrillar collagens have been condsidered as candidate genes for sCAD. We analysed the COL3A1 gene in patients with spontaneous cervical artery dissection (sCAD) and in healthy controls, using three different genetic methods. 1) The promoter region, the 5' and 3' untranscribed regions and the N- and C- peptide encoding regions were studied by direct sequencing analysis of DNA from 12 patients. 2) A possible association of sCAD and the COL3A1 gene was tested for with 5 different DNA polymorphisms in 45 patients and 50 healthy control subjects. 3) DNA samples from a father and his two daughters, all suffering from spontaneous dissections of a cervical artery, were analysed with CA-repeat markers that flank the COL3A1 locus. No disease-causing mutations were found in an extended sequence analysis of the COL3A1 gene in patients with sCAD. However, we identified a single nucleotid polymorphism (SNP) in the promotor region in 2 patients and a 2 bp deletion in the 3' UTR in 7 patients. These sequence variants were also found among 50 healthy subjects. An analysis of multiple DNA polymorphisms of the COL3A1 locus in patients and healthy control persons did not indicate a significant association of sCAD with COL3A1. A deletion polymorphism in the 3' UTR was, however, found more often amongst patients with sCAD. The possible linkage of a hypothetical disease mutation with the COL3A1 locus was tested in a small family with three affected patients. As the affected daughters did not inherit the same COL3A1 allele from their affected father (LOD < - 2.3) COL3A1 was excluded as a disease gene in this family. This study confirms and extends earlier work which suggests that COL3A1 mutations are not a major cause for isolated sCAD.

Adult↗

PubMed2002

Radial perivascular retinal degeneration: a key to the clinical diagnosis of an ocular variant of Stickler syndrome with minimal or no systemic manifestations.

PURPOSE: To identify the genetic defect and present the ocular and extraocular findings in a large pedigree of predominantly ocular Stickler syndrome. DESIGN: Observational case series. METHODS: An eight-generation pedigree with hereditary retinal detachments was retrospectively and prospectively studied. Clinical information was obtained by medical records, telephone interviews, medical questionnaires, detailed ophthalmologic examinations, physical examinations, and personal observations. Linkage analysis of the COL2A1 gene was performed on 21 family members, and mutation analysis was performed on three family members. RESULTS: The pedigree consisted of 100 affected individuals. The ocular findings, frequently bilateral, consisted of radial perivascular retinal degeneration (RPRD) (100%), vitreous syneresis (100%), high myopia (76%), retinal detachment (65%), presenile cataract development (occurring before 50 years of age; 78%), and glaucoma (18%). Most (70%) of the retinal detachments occurred between 4 and 18 years of age. Extraocular manifestations, characteristic for Stickler syndrome, were detected in only four of 100 (4%) affected individuals. Linkage analysis with COL2A1 flanking markers showed evidence for linkage to the COL2A1 locus. The COL2A1 gene analysis identified a mutation converting a codon TGC for cysteine(86) to a premature termination codon in the alternatively spliced exon 2. CONCLUSIONS: A variant of Stickler syndrome, caused by mutations in exon 2 of COL2A1, may present in families with all of the ocular findings and no clinically identifiable extraocular findings associated with Stickler syndrome. The predominant ocular findings are a congenitally abnormal vitreous and an acquired radial perivascular retinal degeneration that may lead to complicated childhood and adult retinal detachment.

Adolescent↗

PubMed2002

Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6.

Primary osteoarthritis (OA) is a common late-onset disease that exhibits complex genetic transmittance. A previous genome-wide linkage scan of OA affected sibling pair families (ascertained by total joint replacement surgery) identified a region of suggestive linkage on chromosome 6, with a maximum multipoint-LOD score (MLS) of 2.9 in 194 families containing sibling pairs concordant for total hip replacement (THR-families). However, up to 50 cM of the chromosome had a multipoint-LOD score >2.0, indicating that the susceptibility locus was poorly mapped. We have now genotyped chromosome 6 to a higher density in an expanded cohort of 378 THR-families. We obtained an MLS of 2.8 to an 11.4 cM interval defined by markers D6S452 and 509-8B2, which map between 70.5 to 81.9 cM from the 6p-telomere. Stratification by gender revealed that this linkage was completely accounted for by female THR-families (n=146), with an MLS of 4.0 and with the highest two-point LOD score being 4.6 for marker D6S1573 (75.9 cM). The 11.4 cM interval just encompasses the candidate gene COL9A1 (81.9 cM). We identified and then genotyped twenty common single nucleotide polymorphisms (SNPs) from within COL9A1 in the 146 probands from our female THR-families and in 215 age-matched female controls. No SNP allele, genotype or haplotype demonstrated association to disease. Overall, we have narrowed the chromosome 6 OA susceptibility locus to a point at which linkage disequilibrium/association analysis is feasible, we have demonstrated that this locus is female specific, and found no evidence that COL9A1 encodes for the susceptibility.

Chromosome Mapping↗

PubMed2002

Genetic risk factors for lumbar disc disease.

Lumbar disc disease (LDD) is a common musculoskeletal disease affecting about 5% of all individuals. It is characterized by lumbar disc herniation, which causes nerve root irritation, either mechanically or via inflammatory mediators, and results in radiating pain, known as sciatica. Numerous studies have been conducted to identify the causes and risk factors for LDD. Lifting heavy loads, torsional stress and motor vehicle driving are among the best-identified environmental risk factors. However, it has become evident recently from family and twin studies that genetic factors may also be important in LDD. This hypothesis was strengthened by the identification of two collagen IX alleles associated with sciatica and lumbar disc herniation. In addition, disc degeneration has been shown to be related to an aggrecan gene polymorphism, a vitamin D receptor and matrix metalloproteinase-3 gene alleles.

Collagen↗

PubMed2001

Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen.

Type I collagen is the most abundant protein in humans, and it helps to maintain the integrity of many tissues via its interactions with cell surfaces, other extracellular matrix molecules, and growth and differentiation factors. Nearly 50 molecules have been found to interact with type I collagen, and for about half of them, binding sites on this collagen have been elucidated. In addition, over 300 mutations in type I collagen associated with human connective tissue disorders have been described. However, the spatial relationships between the known ligand-binding sites and mutation positions have not been examined. To this end, here we have created a map of type I collagen that includes all of its ligand-binding sites and mutations. The map reveals the existence of several hot spots for ligand interactions on type I collagen and that most of the binding sites locate to its C-terminal half. Moreover, on the collagen fibril some potentially relevant relationships between binding sites were observed including the following: fibronectin- and certain integrin-binding regions are near neighbors, which may mechanistically relate to fibronectin-dependent cell-collagen attachment; proteoglycan binding may potentially impact upon collagen fibrillogenesis, cell-collagen attachment, and collagen glycation seen in diabetes and aging; and mutations associated with osteogenesis imperfecta and other disorders show apparently nonrandom distribution patterns within both the monomer and fibril, implying that mutation positions correlate with disease phenotype. These and other observations presented here may provide novel insights into evaluating type I collagen functions and the relationships between its binding partners and mutations.

Amino Acid Sequence↗