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Columbus, OH, United States

Butterfield R.J.,University of Utah | Foley A.R.,University College London | Dastgir J.,U.S. National Institutes of Health | Asman S.,University of Utah | And 9 more authors.
Human Mutation | Year: 2013

Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix. Glycine substitutions in the Gly-X-Y motif in the triple helical domain of COL6A1, COL6A2, or COL6A3 are the most commonly identified mutations in Ullrich congenital muscular dystrophy and Bethlem myopathy. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in this region including clustering of these mutations in a short segment N-terminal to the 17th Gly-X-Y triplet which is associated with increased severity. We hypothesize that this region may represent a functional domain within the triple helix. Published 2013. Wiley Periodicals, Inc. *This article is a U.S. Government work and is in the public domain in the USA. Source

Collins M.P.,Medical College of Wisconsin | Periquet-Collins I.,Medical College of Wisconsin | Sahenk Z.,Center for Gene Therapy | Sahenk Z.,Ohio State University | Kissel J.T.,Ohio State University
Muscle and Nerve | Year: 2010

In suspected vasculitic neuropathy, vasculitis is demonstrated in only 30% of superficial peroneal nerve (SPN)/peroneus brevis muscle (PBM) specimens. Pathologic predictors of vasculitis are thus needed for non-diagnostic cases. Immune deposits in epineurial vessels have an established sensitivity but unknown specificity. In this study we assessed specificity using direct immunofluorescence (DIF) in SPN/PBM biopsies for suspected vasculitic neuropathy. Biopsies from 13 patients with vasculitis, 13 without vasculitis, and 6 with diabetic radiculoplexus neuropathy (DRPN) were stained for immunoglobulin G (IgG), IgM, and complement 3 (C3), and analyzed in a blinded manner. Vascular immunoglobulin or C3 deposits occurred in 12 of 13 nerve or muscle biopsies (11 of 13 nerves, 5 of 13 muscles) in vasculitis vs. 1 of 13 (1 of 13 nerves, 0 of 13 muscles) in controls (P = 0.00003). Specificity was 92%. For DRPN, vascular immune deposits occurred in 5 of 6 nerves or muscles (4 of 6 nerves, 1 of 5 muscles), similar to vasculitis but significantly different from controls. Epineurial/perimysial vascular deposits of immunoglobulin/C3 by DIF are a specific marker of vasculitic neuropathy. © 2010 Wiley Periodicals, Inc. Source

Taylor L.E.,Center for Gene Therapy | Kaminoh Y.J.,Center for Gene Therapy | Rodesch C.K.,University of Utah | Flanigan K.M.,Center for Gene Therapy | Flanigan K.M.,Ohio State University
Neuropathology and Applied Neurobiology | Year: 2012

Aims: Duchenne muscular dystrophy (DMD) is usually associated with absent or nearly absent dystrophin expression at the sarcolemmal membrane. Quantification of very low levels of dystrophin signal in immunofluorescent studies of muscle biopsy sections presents a technical challenge. This is particularly true in the setting of proof-of-principle drug trials, in which the detection and quantification of what may be significant changes in levels of expression is important, even if absolute dystrophin levels remain low. Methods: We have developed a method of image analysis that allows reliable and semi-automated immunofluorescent quantification of low-level dystrophin expression in sections co-stained for spectrin. Using a custom Metamorph script to create a contiguous region spectrin mask, we quantify dystrophin signal intensity only at pixels within the spectrin mask that presumably represent the sarcolemmal membrane. Using this method, we analysed muscle biopsy tissue from a series of patients with DMD, Becker muscular dystrophy, intermediate muscular dystrophy and normal control tissue. Results: Analysis of serial sections on multiple days confirms reproducibility, and normalized dystrophin:spectrin intensity ratios (expressed as a percentage of normal control tissue) correlate well with the dystrophin expression levels as determined by Western blot analysis. Conclusion: This method offers a robust and reliable method of biomarker detection for trials of DMD therapies. © 2012 British Neuropathological Society. Source

Marcadenti A.,Federal University of Rio Grande do Sul | Fuchs F.D.,Federal University of Rio Grande do Sul | Fuchs F.D.,Brazilian National Council for Scientific and Technological Development | Matte U.,Center for Gene Therapy | And 5 more authors.
Cardiovascular Diabetology | Year: 2013

Background: Genetic variants of the FTO gene rs9939609 A/T and the MC4R gene rs17782313 C/T have been associated with obesity. Individuals with mutations in MC4R gene have lower blood pressure (BP), independently of obesity. This study aimed to investigate the association of FTO rs9939609 and MC4R rs17782313 with anthropometric indexes, BP, and type 2 diabetes mellitus among hypertensive patients.Methods: We genotyped 217 individuals (86 men and 131 women) with hypertension (systolic or diastolic BP ≥ 140/90 mmHg or using antihypertensive drugs). Diabetes mellitus was diagnosed according to the American Diabetes Association criteria. Waist and neck circumferences (cm), Body Adiposity Index (BAI,%), Lipid Accumulation Product Index (LAP, cm.mmol.l) and body mass index (BMI, kg/m2) were analyzed using analysis of covariance or modified Poisson's regression.Results: Rare allele frequencies were 0.40 for A for FTO rs9939609 and 0.18 for C for MC4R rs17782313. A positive association of FTO rs9939609 and MC4R rs17782313 with BMI was observed in the overall sample. Among men and women, neck circumference was associated with the FTO genotype and, for women, MC4R genotype. In contrast, in men we found a negative association of MC4R rs17782313 with diastolic BP (TT 90.1 ±12.2, TC/CC 83.2 ±12.1; P = 0.03) and borderline association for systolic BP after controlling for age and BMI.Conclusions: Common genetic variants of FTO rs9939609 have positive associations with BMI and neck circumference and MC4R rs17782313 in women, but a negative association with diastolic and mean blood pressure in men with hypertension. © 2013 Marcadenti et al.; licensee BioMed Central Ltd. Source

Flanigan K.M.,Center for Gene Therapy | Voit T.,University Pierre and Marie Curie | Rosales X.Q.,Center for Gene Therapy | Servais L.,University Pierre and Marie Curie | And 10 more authors.
Neuromuscular Disorders | Year: 2014

Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2'- O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ≥9. years, in wheelchairs for ≥1 to ≤4. years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12. mg/kg), but study objectives were met with the 9. mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3-9. mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3-6. mg/kg range. Single doses of drisapersen at 3 and 6. mg/kg did not result in significant safety or tolerability concerns; however, at the 9. mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6. mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. © 2013 The Authors. Source

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