Identification of five novel mutations in cartilage oligomeric matrix protein gene in pseudoachondroplasia and multiple epiphyseal dysplasia.
Explore the source record for details and available documents.
Achondroplasia↗
Biomedical subjects
R G Knowlton
Publications and source records attributed to R G Knowlton.
Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum.
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are autosomal dominant osteochondrodysplasias that result in mild to severe short-limb dwarfism and early-onset osteoarthrosis. PSACH and some forms of MED result from mutations in the gene for cartilage oligomeric matrix protein (COMP; OMIM 600310 [http://www3.ncbi.nlm. nih.gov:80/htbin-post/Omim/dispmim?600310]). We report the identification of COMP mutations in an additional 14 families with PSACH or MED phenotypes. Mutations predicted to result in single-amino acid deletions or substitutions, all in the region of the COMP gene encoding the calmodulin-like repeat elements, were identified in patients with moderate to severe PSACH. We also identified within this domain a missense mutation that produced MED Fairbank. In two families, one with mild PSACH and the second with a form of MED, we identified different substitutions for a residue in the carboxyl-terminal globular region of COMP. Both the clinical presentations of these two families and the identification of COMP-gene mutations provide evidence of phenotypic overlap between PSACH and MED. These data also reveal a role for the carboxyl-terminal domain in the structure and/or function of COMP.
Achondroplasia↗
Effects of dehydration on isometric muscular strength and endurance.
To examine the effects of rapid dehydration on isometric muscular strength and endurance, seven men were tested at baseline (control) and after a dehydration (dHST) and a euhydration (eHST) heat stress trial. The dHST consisted of intermittent sauna exposure until 4% of body mass was lost, whereas the eHST consisted of intermittent sauna exposure (same duration as dHST) with water replacement. Peak torque was determined for the knee extensors and elbow flexors during three isometric maximal voluntary contractions. Time to fatigue was determined by holding a maximal voluntary contraction until torque dropped below 50% peak torque for 5 s. Strength and endurance were assessed 3.5 h after the HSTs (no food or water intake). Body mass was decreased 3.8+/-0.4% post dHST and 0.4+/-0.3% post eHST. Plasma volume was decreased 7.5+/-4.6% and 5.7+/-4.4%, 60 and 120 min post dHST, respectively. A small (1.6 mEq x L[-1]) but significant increase was found for serum Na+ concentration 60 min post dHST but had returned to predehydration level 120 min post dHST. Serum K+ and myoglobin concentrations were not affected by HSTs. Peak torque was not different (P > 0.05) among control, dHST, and eHST for the knee extensors (Mean (Nm)+/-SD, 285+/-79, 311+/-113, and 297+/-79) and elbow flexors (79+/-12, 83+/-15, and 80+/-12). Time to fatigue was not different (P > 0.05) among control, dHST and eHST for the knee extensors (Mean (s)+/-SD. 42.4+/-11.5, 45.3+/-7.6, and 41.8+/-6.0) and elbow flexors (48.2+/-8.9, 44.0+/-9.4, and 46.0+/-6.4). These results provide evidence that isometric strength and endurance are unaffected 3.5 h after dehydration of approximately 4% body mass.
Adult↗
Identifying the integrated electromyographic threshold using different muscles during incremental cycling exercise.
BACKGROUND: The purpose of this study was to identify the IEMG threshold in the vastus lateralis (VL) and rectus femoris (RF) muscles during progressive, incremental exercise and to relate these thresholds to the ventilatory threshold (Tvent). METHODS: Ten men (age: 23.40 +/- 3.13 yrs, mass 76.64 +/- 8.13 kg, % fat: 8.81 +/- 2.32, VO2peak: 66.37 +/- 10.61 ml.kg.min-1) with cycling experience completed a graded exercise test on a cycle ergometer by cycling at 90 rpm using 45 watt increments at two minute intervals. Oxygen uptake was measured continuously and the IEMG activity of the VL and RF was calculated during the last 5 s of each minute. The mean for the IEMG of 6 to 7 complete pedal revolutions was used as the final value. Tvent was visually identified using the VE/VO2 and V-slope methods. The IEMG threshold for VL and RF was visually identified at the inflection point where a non-linear increase in IEMG occurred. Comparisons between Tvent and IEMG thresholds were made using dependent means "t"-tests. RESULTS: Results showed that an IEMG threshold was identified in all 10 subjects for the RF, but in only 5 of 10 subjects for the VL. However, when identified, the IEMG threshold for VL was similar to RF.VO2 at IEMG threshold for RF (3.53 +/- 0.36 L.min-1) was not significantly different from Tvent (3.36 +/- 0.42 L.min-1). CONCLUSIONS: These results show that the IEMG threshold is more consistently detected in the RF compared to VL during incremental cycling exercise. In addition, the IEMG threshold for RF was closely related to Tvent and provides an alternative means to assess the ventilatory threshold.
Adult↗
Multiple epiphyseal dysplasia, ribbing type: a novel point mutation in the COMP gene in a South African family.
Multiple epiphyseal dysplasia is broadly categorised into the more severe Fairbank and the milder Ribbing types. In this paper we document mild MED in a South African kindred, and demonstrate that heterozygosity for a mutation in the cartilage oligomeric matrix protein (COMP) gene causes the condition. The mutation, C1594G, implies a N523K substitution, altering a residue at the carboxyl-terminal end of the calmodulin-like region of COMP. The identification of this mutation demonstrates that the spectrum of manifestations from mild MED through pseudoachondroplasia can all be produced by structural mutations in COMP.
Adult↗
Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy.
The intermediate filament cytoskeleton of corneal epithelial cells is composed of cornea-specific keratins K3 and K12 (refs 1,2). Meesmann's corneal dystrophy (MCD) is an autosomal dominant disorder causing fragility of the anterior corneal epithelium, where K3 and K12 are specifically expressed. We postulated that dominant-negative mutations in these keratins might be the cause of MCD. K3 was mapped to the type-II keratin gene cluster on 12q; and K12 to the type-I keratin cluster on 17q using radiation hybrids. We obtained linkage to the K12 locus in Meesmann's original German kindred (Zmax = 7.53; theta = 0) and we also showed that the phenotype segregated with either the K12 or the K3 locus in two Northern Irish pedigrees. Heterozygous missense mutations in K3 (E509K) and in K12 (V143L; R135T) completely co-segregated with MCD in the families and were not found in 100 normal unrelated chromosomes. All mutations occur in the highly conserved keratin helix boundary motifs, where dominant mutations in other keratins have been found to severely compromise cytoskeletal function, leading to keratinocyte fragility phenotypes. Our results demonstrate for the first time the molecular basis of Meesmann's corneal dystrophy.
Cornea↗
Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling.
Achromatopsia is an autosomal recessive disease of the retina, characterized clinically by an inability to distinguish colors, impaired visual acuity, nystagmus and photophobia. A genome-wide search for linkage was performed using an inbred Jewish kindred from Iran. To facilitate the genome-wide search, we utilized a DNA pooling strategy which takes advantage of the likelihood that the disease in this inbred kindred is inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as the PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pool was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest LOD score observed was 5.4 (theta = 0). When four additional small unrelated families were genotyped, the combined peak LOD score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30 cM interval which spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. A candidate gene for achromatopsia was excluded from this disease interval by radiation hybrid mapping. Linkage of achromatopsia to chromosome 2 is an essential first step in the identification of the disease-causing gene.
Chromosome Mapping↗
The effect of exercise induced glycogen depletion on the lactate, ventilatory and electromyographic thresholds.
BACKGROUND: This study compared the integrated electromyogram (IEMG), lactate, and ventilatory thresholds under normal glycogen (NG) and depleted glycogen (DG) conditions for the purpose of determining the presence of a possible relationship between neuromuscular, metabolic and respiratory thresholds. MATERIALS AND METHODS: Six trained, male cyclists (Age = 24.0 +/- 2.45 yrs, Ht = 1.76 +/- 0.84 m, Mass = 76.22 +/- 10.03 kg, % Fat = 8.57 +/- 1.50, VO2 peak = 68.97 +/- 10.46 ml . kg-1 . min-1) completed a progressive, incremental cycle ergometer test under NG and DG conditions in a randomized order. Glycogen depletion was accomplished by having the subjects: (1) engage in a 12 hour fast prior to the exercise test, (2) complete a 1.5 hour ride at their ventilatory threshold, and (3) complete 4 to 8 one-minute rides at 100% of VO2 peak. Six hours following the depletion rides, the subjects completed the exercise test (90 rpm, 45 watts/2 min). Blood was withdrawn through a forearm venous catheter each minute and later analyzed for blood lactate. Metabolic data were measured every 30s and the IEMG of the rectus femoris was recorded during the last 10s of each minute of the exercise test. Results showed that under NG, the IEMG (TIEMG), lactate (Tlac), and ventilatory (Tvent) thresholds occurred at a similar VO2 (TIEMG = 3.46 +/- 0.31, Tlac = 3.51 +/- 0.34, Tvent = 3.36 +/- 0.42 L . min-1). However, under DG there was a significant shift in the TIEMG to a higher VO2 (TIEMG = 4.41 +/- 0.54 L . min-1 = p 0.003). Tlac was not significantly greater following glycogen depletion, but had shifted to a higher VO2 in relation to the Tvent (Tlac = 3.96 +/- 0.40 L . min-1, Tvent = 3.37 +/- 0.64 L . min-1 = p 0.01). These data show that lactate accumulation and muscle activation of the vastus lateralis and rectus femoris are not the controlling mechanisms of the ventilatory threshold during progressive, incremental cycling exercise.
3-Hydroxybutyric Acid↗
Mutations in the cartilage oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal dysplasia.
Explore the source record for details and available documents.
Amino Acid Sequence↗
High-resolution genetic and physical mapping of multiple epiphyseal dysplasia and pseudoachondroplasia mutations at chromosome 19p13.1-p12.
Multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH) are autosomal dominant chondrodysplasias that have similar phenotypes at both clinical and cytological levels. With the recent mapping of PSACH and one form of MED (EDM1) to the pericentromeric region of chromosome 19, it is likely that the disease mutations are allelic. D19S212 and D19S215, genetic markers flanking the EDM1/PSACH locus, have been localized in a chromosome 19 physical map consisting of cosmid contigs ordered by high-resolution FISH. These two markers define an interval of approximately 3.1 Mb at the 19p13.1-p12 boundary. With as many as five informative crossovers within the D19S212-D19S215 interval in one family with EDM1 and one family with a mild form of PSACH, recombination mapping at greater resolution was undertaken. From cosmid contigs physically mapped within the D19S212-D19S215 interval, four new dinucleotide repeat polymorphisms have been identified. Analysis of recombinant haplotypes in the two families has narrowed the possible location of the EDM1/PSACH gene to an interval of approximately 600 kb.
Base Sequence↗
D20S16 is a complex interspersed repeated sequence: genetic and physical analysis of the locus.
The genomic structure of the D20S16 locus has been evaluated using genetic and physical methods. D20S16, originally detected with the probe CRI-L1214, is a highly informative, complex restriction fragment length polymorphism consisting of two separate allelic systems. The allelic systems have the characteristics of conventional VNTR polymorphisms and are separated by recombination (theta = 0.02, Zmax = 74.82), as demonstrated in family studies. Most of these recombination events are meiotic crossovers and are maternal in origin, but two, including deletion of the locus in a cell line from a CEPH family member, occur without evidence for exchange of flanking markers. DNA sequence analysis suggests that the basis of the polymorphism is variable numbers of a 98-bp sequence tandemly repeated with 87 to 90% sequence similarity between repeats. The 98-bp repeat is a dimer of 49 bp sequence with 45 to 98% identity between the elements. In addition, nonpolymorphic genomic sequences adjacent to the polymorphic 98-bp repeat tracts are also repeated but are not polymorphic, i.e., show no individual to individual variation. Restriction enzyme mapping of cosmids containing the CRI-L1214 sequence suggests that there are multiple interspersed repeats of the CRI-L1214 sequence on chromosome 20. The results of dual-color fluorescence in situ hybridization experiments with interphase nuclei are also consistent with multiple repeats of an interspersed sequence on chromosome 20.
Alleles↗
Stickler syndrome. A mutation in the nonhelical 3' end of type II procollagen gene.
BACKGROUND: All of the mutations in the type II procollagen (COL2A1) gene that have been identified in families affected with Stickler syndrome have been located primarily in the triple helical region of the gene. We report what we believe is the first premature stop codon in the globular C-propeptide region encoded by the COL2A1 gene, in a family affected with Stickler syndrome. DESIGN: Genomic DNA from affected and unaffected family members of this three-generation family was amplified using the polymerase chain reaction. The polymerase chain reaction products were directly sequenced for DNA analysis. RESULTS: Direct sequencing showed a single base deletion in exon 50, resulting in a premature stop codon in exon 51 in the globular C-propeptide of COL2A1 gene in all affected members. CONCLUSIONS: These results implicate premature stop codons as a common cause of Stickler syndrome. The location of this premature stop codon in the far end of the nonhelical 3' end of the gene indicates that a truncated C-propeptide of at least 84 amino acid residues is inadequate for the functional gene product.
Adolescent↗
Prenatal exclusion of Stickler syndrome.
Stickler syndrome is an autosomal dominant disorder of the connective tissue which includes ocular and systemic manifestations. We report on a large kindred in which we were able to demonstrate very tight linkage between the disease and the type II collagen gene (COL2A1) (LOD score 3.91 at theta = 0). In a family in which the father and one of his daughters were severely affected, DNA analysis from a chorionic villus sample demonstrated that the fetus possessed the normal allele of COL2A1. Thereafter a normal child was born.
Chorionic Villi Sampling↗
Perception of effort during high-intensity exercise at low, moderate and high wet bulb globe temperatures.
The purpose of this study was to determine the effect of low, moderate and high wet bulb globe temperatures (Twbg) on cardiovascular variables and ratings of perceived exertion (RPE) during moderately prolonged, high-intensity exercise. Six subjects [four men and two women; mean (SD) age, 22.0 (1.2) years; maximum oxygen consumption (VO2peak), 51.0 (8.4) ml.kg-1.min-1] completed 30 min of exercise (80% VO2peak) on a cycle ergometer at low [14.7 (2.1) degrees C], moderate [21.0 (1.5) degrees C], and high [27.4 (2.3) degrees C] Twbg. Two additional subjects completed 20 min of exercise in the high temperature condition, but completed 30 min in the moderate and low Twbg. Heart rate (fc), blood pressure, blood lactate (La), mean skin temperature (Tsk), VO2, and RPE were measured at 10, 20 and 30 min. Results showed that fc, rate pressure product, RPE, pulmonary ventilation and ventilatory equivalent for oxygen increased (P < 0.05) across time for all conditions, while P(a) decreased across time. Tsk and fc were significantly greater across time in the high condition [35.9 (0.65) degrees C; 176 (12.6) beats.min-1] compared to the moderate [34.6 (1.5) degrees C; 170 (17.2) beats.min-1] and the low condition [31.7 (1.5) degrees C; 164 (17.1) beats.min-1]. However, there were no differences throughout exercise in RPE [high, 16.2 (2.0); moderate, 16.4 (2.2); low, 16.3 (1.9)] and VO2 across the conditions. These data suggest that RPE is closely related to metabolic intensity but is not a valid indicator of cardiovascular strain during exercise in high Twbg conditions.
Adult↗
Effect of concurrent exercise and physostigmine on lactate and pyruvate in plasma, muscle, and brain tissue of rats.
The purpose of this investigation was to determine the effect of physostigmine (Phy) and/or concurrent exercise on lactate, pyruvate, and L/P ratio in plasma, skeletal muscle, and brain tissue in male Sprague-Dawley rats. The Phy-dosed (Phy-D) and Phy-dosed + concurrent acute exercise (Phy-D + CAE) groups elicited significantly higher L/P ratios in plasma compared to the acutely exercised (AE) group at 30 min postexercise. Physostigmine dosing, with or without exercise, resulted in significantly lower muscle pyruvate levels, from 30 to 50 min postdrug administration, in Phy-D and Phy-D + CAE groups compared to the AE group. In the brain, lactate values were significantly elevated in the acutely exercised groups at 5 min postexercise with or without Phy dosing. However, at 15 to 30 min postexercise, lactate values were significantly elevated in the Phy-D + CAE compared to the AE group. These data suggest that when Phy is administered prior to a 20-min moderately intensive exercise bout, there is an accumulation of lactate for a prolonged period of time in recovery.
Animals↗
Anthropometric characteristics and performance related predictors of success in adolescent pole vaulters.
The purpose of this study was to determine the anthropometric characteristics of skilled adolescent pole vaulters and to examine the strength of anthropometric and physical performance variables in predicting vaulting performance (N = 87; age group range 13-18 years). The vaulting height of the subjects ranged from 1.98 to 4.72m (mean 3.58 +/- s.d. 0.536m). The vaulters were classified as ectomorphic mesomorphs with an average somatotype of 1.6-4.2-3.5 (s.d. +/- 0.38-0.94-1.00). One way analysis of variance showed that while measures of stature, physical performance and vault performance significantly increased (p < 0.05) across age groups, somatotype and sum of skinfolds remained stable. Stepwise regression analysis showed the best predictor of vaulting performance was hand grip height (R2 = 0.78, p < 0.05). Correlation analysis showed that grip height was strongly correlated to vault height (r = 0.88), age (r = 0.72), body mass (r = 0.71), standing long jump (r = 0.69), running speed (r = 0.69), biceps girth (r = 0.66), standing height (0.65), calf girth (0.61) and pull-ups (r = 0.44). It was concluded that the somatotype of skilled young pole vaulters is similar to that of junior Olympic and adult Olympic vaulters, and that this somatotype is a selective factor for this event as early as thirteen years of age. Proficiency in pole vaulting is best predicted by grip height, which is strongly correlated to stature and simple field measures of leg speed and power, and upper body muscular endurance. These findings may be applied to the selection and training of young pole vaulters.
Adolescent↗
Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19.
Multiple epiphyseal dysplasia (MED) is an inherited chondrodystrophy that results in deformity of articular surfaces and in subsequent degenerative joint disease. The disease is inherited as an autosomal dominant trait with high penetrance. An MED mutation has been mapped by genetic linkage analysis of DNA polymorphisms in a single large pedigree. Close linkage of MED to 130 tested chromosomal markers was ruled out by discordant inheritance patterns. However, strong evidence for linkage of MED to markers in the pericentromeric region of chromosome 19 was obtained. The most closely linked marker was D19S215, with a maximum LOD score of 6.37 at theta = .05. Multipoint linkage analysis indicated that MED is located between D19S212 and D19S215, a map interval of 1.7 cM. Discovery of the map location of MED in this family will facilitate identification of the mutant gene. The closely linked DNA polymorphisms will also provide the means to determine whether other inherited chondrodystrophies have underlying defects in the same gene.
Centromere↗
Exclusion of type II and type VI procollagen gene mutations in a five-generation family with multiple epiphyseal dysplasia.
We have studied a family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) inherited through at least 5 generations. Bilateral deformity of the hips with subsequent degenerative arthritis was the most common and most severe change observed in the affected relatives. Abnormalities of the knees, ankles, and shoulders were also noted in some affected individuals. Radiological examination showed changes in affected joints consistent with epiphyseal dysplasia. In early stages, the articular surfaces appeared flattened or irregular in shape. In advanced stages, epiphyseal fragmentation, joint surface erosion, and extensive remodeling were observed. The abnormalities of the epiphyses suggested that the primary defect might be in a structural component of the epiphyseal cartilage matrix. The gene encoding type II collagen (COL2A1) was tested for genetic linkage to MED in this family by restriction fragment length polymorphism (RFLP) analysis. Recombination between COL2A1 and MED was observed, ruling out COL2A1 as the site of the mutation. The genes encoding the 3 chains of type VI collagen were also excluded on the basis of discordant inheritance. The disease in this family is therefore not the result of mutations in the genes encoding type II or type VI collagen.
Adult↗