A5043625969- Muscle Physiology and Disorders
- Cell Adhesion Molecules Research
- Cardiomyopathy and Myosin Studies
- Cellular Mechanics and Interactions
- Connective tissue disorders research
- Neurogenetic and Muscular Disorders Research
- Inflammatory Myopathies and Dermatomyositis
- Tissue Engineering and Regenerative Medicine
- Skin and Cellular Biology Research
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Biotin and Related Studies
- Nuclear Structure and Function
- Knee injuries and reconstruction techniques
- Osteoarthritis Treatment and Mechanisms
- RNA Interference and Gene Delivery
- Hereditary Neurological Disorders
- Congenital limb and hand anomalies
- Cellular transport and secretion
- Protease and Inhibitor Mechanisms
- Dermatological and Skeletal Disorders
- CAR-T cell therapy research
- Galectins and Cancer Biology
- Plant biochemistry and biosynthesis
- Molecular Biology Techniques and Applications
National Institutes of Health
2012-2025
National Institute of Neurological Disorders and Stroke
2012-2025
Shenyang Sujiatun District Central Hospital
2024
Bioscience (China)
2023
Ocean University of China
2017-2019
Thomas Jefferson University
2008-2011
Children's Hospital of Philadelphia
2004-2010
University of Pennsylvania
2004-2010
Philadelphia University
2006-2010
Clayton Foundation
2009
Reducing body myopathy (RBM) is a rare disorder causing progressive muscular weakness characterized by aggresome-like inclusions in the myofibrils. Identification of genes responsible for RBM traditional genetic approaches has been impossible due to frequently sporadic occurrence affected patients and small family sizes. As an alternative approach gene identification, we used laser microdissection intracytoplasmic identified patient muscle biopsies, followed nanoflow liquid...
Mutations in the extracellular matrix molecule collagen VI underlie congenital muscular dystrophy types Ullrich and Bethlem. Establishing origin of muscle is important for understanding pathophysiology these diseases developing future treatment approaches involving cell-specific delivery. Because cells that produce cannot be identified by histologic analysis, we examined production pure cultures primary myogenic interstitial fibroblasts from limb neonatal mice. Immunofluorescence staining...
Collagen VI-related myopathies are disorders of connective tissue presenting with an overlap phenotype combining clinical involvement from the muscle and tissue. Not all patients displaying related phenotypes between have mutations in collagen VI. Here, we report a homozygous recessive loss function mutation de novo dominant XII (COL12A1) as underlying novel syndrome involving Two siblings for showed widespread joint hyperlaxity combined weakness precluding independent ambulation, while...
Regulators of skeletal muscle mass are interest, given the morbidity and mortality atrophy myopathy. Four-and-a-half LIM protein 1 (FHL1) is mutated in several human myopathies, including reducing-body myopathy (RBM). The normal function FHL1 how it causes remains unknown. We find that transgenic expression mouse promotes hypertrophy an oxidative fiber-type switch, leading to increased whole-body strength fatigue resistance. Additionally, overexpression enhances myoblast fusion, resulting...
Bethlem myopathy (BM) [MIM 158810] is a slowly progressive muscle disease characterized by contractures and proximal weakness, which can be caused mutations in one of the collagen VI genes (COL6A1, COL6A2 COL6A3). However, there may additional causal to identify as ∼50% BM cases no COL6 are identified. In cohort –24 patients with BM-like phenotype, we first sequenced 12 candidate based on their function, including for known binding partners VI, those enzymes involved its correct...
Glycine substitutions in the conserved Gly-X-Y motif triple helical (TH) domain of collagen VI are most commonly identified mutations myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical genetic characteristics 97 individuals with glycine TH COL6A1, COL6A2, or COL6A3 add a review published cases, for total 194 cases. Clinical findings include severe, INT, mild phenotypes even from patients identical mutations....
Abstract Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in the three genes coding for alpha chains of collagen VI and characterized generalized muscle weakness, striking hypermobility distal joints conjunction with variable contractures more proximal joints, normal intellectual development. The diagnosis supported abnormal immunoreactivity on biopsies. As patients UCMD show clinical characteristics typical classical disorders connective tissue such as Ehlers–Danlos...
We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as causative for reducing body myopathy, disorder characterized by progressive weakness intracytoplasmic aggregates in muscle that exert activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected affected highly conserved zinc coordinating residues within second lead to formation of when transfected into cells. Our aim was define clinical morphological phenotype this myopathy assess mutational...
Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) Ullrich congenital muscular dystrophy (UCMD), two related conditions of differing severity. BM is a relatively mild dominantly inherited disorder characterized by proximal weakness distal joint contractures. UCMD was originally regarded as an exclusively autosomal recessive condition causing severe muscle with contractures hyperlaxity. We others have subsequently modified this model when we...
Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of triple helical domain collagens. P4HA1 encodes catalytic α(I) subunit main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic mutations family with congenital-onset disorder connective tissue, manifesting as early-onset joint hypermobility, contractures, muscle weakness bone dysplasia well high myopia, evidence clinical improvement motor function over time surviving patient. Similar to...
Abstract The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes component the that interacts with perlecan/collagen VI, appears to be involved in stabilizing structures, demonstrates high expression levels tibial nerve. Vwa1-deficient mice manifest abnormal peripheral nerve structure/function; however, variants have not previously been associated human disease. By...
While there have been several reports of patients with dominantly acting COL12A1 variants, few cases the more severe recessive Collagen XII-related disorders previously documented. We present detailed clinical, immunocytochemical, and imaging data on eight additional from seven families biallelic pathogenic variants in COL12A1. All presented a consistent constellation congenital onset clinical features: hypotonia, dysmorphic features, most notably gingival hypertrophy, prominent distal joint...
New genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated the present study was described 1966 expands phenotype of known neuromuscular gene.To determine cause slowly progressive, autosomal dominant, scapuloperoneal disorder by using linkage exome sequencing.Fourteen affected individuals 6-generation progressive were evaluated. Participants examined at pediatric, neuromuscular,...
Mutations in the COL12A1 (collagen, type XII, alpha 1) gene have been described a milder Bethlem-like myopathy 6 patients from 3 families (dominant missense), and severe congenital form with failure to attain ambulation 2 single pedigree (recessive loss-of-function).We describe an 8-year-old girl of Polish origin who presented profound hypotonia joint hyperlaxity at birth after pregnancy complicated by oligohydramnios intrauterine growth retardation.We identified novel, potentially...
To characterize the natural history and clinical features of myopathies caused by mono-allelic, dominantly acting pathogenic variants in COL12A1.Patients with dominant COL12A1-related were characterized examination, muscle imaging, genetic analysis. Pathogenicity was assessed immunostaining patient-derived dermal fibroblast cultures for collagen XII.Four independent families childhood-onset weakness due to novel, COL12A1 identified. Adult patients exhibited distal-predominant weakness. Three...
A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings subsequent patients a similar constellation findings. The goal this study to understand the genetic molecular etiology condition.
Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively-acting mutations and recessively-acting loss-of-function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A2is not disease mechanism Bethlem...
Reducing body myopathy (RBM) is a rare progressive disorder of muscle characterized by intracytoplasmic inclusions, which stain strongly with menadione-NBT (nitroblue tetrazolium). We recently identified the four and half LIM domain gene FHL1 located on chromosome Xq26 as causative for RBM. So far eight familial cases 21 sporadic patients RBM have been reported in literature.We ascertained total 8 members German family initially Goebel et al. mixed rigid spine reducing well cytoplasmic...