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Carsten G Bönnemann

Publications and source records attributed to Carsten G Bönnemann.

15 recordsLinked to original sources
PubMed2006

MRI in DNM2-related centronuclear myopathy: evidence for highly selective muscle involvement.

Dynamin 2 has recently been recognized as a causative gene for the autosomal dominant form of centronuclear myopathy (dominant centronuclear myopathy). Here we report an affected father and daughter with dynamin 2 related AD CNM with predominantly distal onset of weakness. In addition to the diagnostic central location of myonuclei the muscle biopsy also showed core-like structures. Muscle MRI in the lower leg revealed prominent involvement of the soleus, but also of the gastrocnemius and the tibialis anterior whereas in the thigh there was a consistent pattern of selective involvement of adductor longus, semimembranosus, biceps femoris, rectus femoris, and vastus intermedius with relative sparing of vastus lateralis and medialis, sartorius, gracilis, and partly of the semitendinosus. These characteristic findings on muscle MRI confirm similar findings reported for CT imaging in dynamin 2 related dominant centronuclear myopathy and may help to differentiate this disorder from central core disease and other myopathies.

Adult↗
PubMed2006

Identification of functional domains in sarcoglycans essential for their interaction and plasma membrane targeting.

Mutations in sarcoglycans have been reported to cause autosomal-recessive limb-girdle muscular dystrophies. In skeletal and cardiac muscle, sarcoglycans are assembled into a complex on the sarcolemma from four subunits (alpha, beta, gamma, delta). In this report, we present a detailed structural analysis of sarcoglycans using deletion study, limited proteolysis and co-immunoprecipitation. Our results indicate that the extracellular regions of sarcoglycans consist of distinctive functional domains connected by proteinase K-sensitive sites. The N-terminal half domains are required for sarcoglycan interaction. The C-terminal half domains of beta-, gamma- and delta-sarcoglycan consist of a cysteine-rich motif and a previously unrecognized conserved sequence, both of which are essential for plasma membrane localization. Using a heterologous expression system, we demonstrate that missense sarcoglycan mutations affect sarcoglycan complex assembly and/or localization to the cell surface. Our data suggest that the formation of a stable complex is necessary but not sufficient for plasma membrane targeting. Finally, we provide evidence that the beta/delta-sarcoglycan core can associate with the C-terminus of dystrophin. Our results therefore generate important information on the structure of the sarcoglycan complex and the molecular mechanisms underlying the effects of various sarcoglycan mutations in muscular dystrophies.

Amino Acid Sequence↗
PubMed2006

Congenital muscular dystrophies and the extracellular matrix.

During the past decade, considerable progress in the field of congenital muscular dystrophies (CMDs) had led to the identification of a growing number of causative genes. This genetic progress has uncovered crucial pathophysiological concepts and has been instrumental in redefining clinical phenotypes. Important new pathogenic mechanisms include the disorders of O-mannosyl-linked glycosylation of alpha-dystroglycan as well as the involvement of a collagen type VI in the pathogenesis of congenital disorders of muscle. Thus, an emerging theme among gene products involved in the pathogenesis of congenital muscular dystrophy is their intimate connection to the extracellular matrix. In this review, we focus on the clinical phenotypes that we are correlating with the novel genetic and biochemical findings encountered within CMD. This correlation will frequently lead to a considerably expanded clinical spectrum associated with a given CMD gene.

Animals↗
PubMed2005

Ullrich congenital muscular dystrophy: connective tissue abnormalities in the skin support overlap with Ehlers-Danlos syndromes.

Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in the three genes coding for the alpha chains of collagen VI and characterized by generalized muscle weakness, striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints, and normal intellectual development. The diagnosis is supported by abnormal immunoreactivity for collagen VI on muscle biopsies. As patients with UCMD show clinical characteristics typical of classical disorders of connective tissue such as Ehlers-Danlos syndromes (EDS), we investigated the ultrastructure of skin biopsy samples from patients with UCMD (n=5). Electron microscopy of skin biopsies revealed ultrastructural abnormalities in all cases, including alterations of collagen fibril morphology (variation in size and composite fibers) and increase in ground substance, which resemble those seen in patients with EDS. Our findings suggest that there is a true connective tissue component as part of the phenotypic spectrum of UCMD and that there is considerable clinical as well as morphological overlap between UCMD and classic connective tissue disorders.

Adolescent↗
PubMed2005

p.S143F mutation in lamin A/C: a new phenotype combining myopathy and progeria.

We report a young girl with a phenotype combining early-onset myopathy and a progeria. She had myopathy and marked axial weakness during the first year of life; progeroid features, including growth failure, sclerodermatous skin changes, and osteolytic lesions, developed later. We identified the underlying cause to be a hitherto unreported de novo missense mutation in the LMNA gene (S143F) encoding the nuclear envelope proteins lamins A and C. Although LMNA mutations have been known to cause Hutchinson-Gilford progeria syndrome and Emery-Dreifuss muscular dystrophy, this is the first report of a patient combining features of these two phenotypes because of a single mutation in LMNA.

Blotting, Western↗
PubMed2005

Limb-girdle muscular dystrophy in childhood.

LGMD refers to a class of muscular dystrophies with onset in the proximal muscles. They are genetically heterogeneous, with both autosomal recessive and dominant forms. The autosomal recessive forms are more common and in general follow a more severe course compared to the dominant forms. It is important to reach a specific genetic diagnosis beyond making a group diagnosis of LGMD to provide adequate genetic counseling, to predict risks for the patient such as the development of cardiomyopathy, and to be able to take advantage of specific treatments when they become available. Establishing a specific diagnosis requires knowledge about the individual clinical features, expert analysis of the muscule biopsy, and the guided initiation of appropriate genetic testing.

Biopsy↗
PubMed2004

Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments.

Contractile myocytes provide a test of the hypothesis that cells sense their mechanical as well as molecular microenvironment, altering expression, organization, and/or morphology accordingly. Here, myoblasts were cultured on collagen strips attached to glass or polymer gels of varied elasticity. Subsequent fusion into myotubes occurs independent of substrate flexibility. However, myosin/actin striations emerge later only on gels with stiffness typical of normal muscle (passive Young's modulus, E approximately 12 kPa). On glass and much softer or stiffer gels, including gels emulating stiff dystrophic muscle, cells do not striate. In addition, myotubes grown on top of a compliant bottom layer of glass-attached myotubes (but not softer fibroblasts) will striate, whereas the bottom cells will only assemble stress fibers and vinculin-rich adhesions. Unlike sarcomere formation, adhesion strength increases monotonically versus substrate stiffness with strongest adhesion on glass. These findings have major implications for in vivo introduction of stem cells into diseased or damaged striated muscle of altered mechanical composition.

Acrylic Resins↗
PubMed2004

The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries.

During the past decade, outstanding progress in the areas of congenital and limb-girdle muscular dystrophies has led to staggering clinical and genetic complexity. With the identification of an increasing number of genetic defects, individual entities have come into sharper focus and new pathogenic mechanisms for muscular dystrophies, like defects of posttranslational O-linked glycosylation, have been discovered. At the same time, this progress blurs the traditional boundaries between the categories of congenital and limb-girdle muscular dystrophies, as well as between limb-girdle muscular dystrophies and other clinical entities, as mutations in genes such as fukutin-related protein, dysferlin, caveolin-3 and lamin A/C can cause a striking variety of phenotypes. We reviewed the different groups of proteins currently recognized as being involved in congenital and limb-girdle muscular dystrophies, associated them with the clinical phenotypes, and determined some clinical and molecular clues that are helpful in the diagnostic approach to these patients.

Adolescent↗
PubMed2004

Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene.

Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.

Adult↗
PubMed2004

Myopathies resulting from mutations in sarcomeric proteins.

PURPOSE OF REVIEW: The past decade has seen the discovery of the major role that mutations in the protein components of the sarcomere plays as a cause of human muscle disease. An overview of the more precise molecular definitions of these diseases is timely. RECENT FINDINGS: Recent findings include: the beginnings of an understanding of the role of the sarcomere in controlling muscle gene expression; the theoretical analysis of the increasing number of mutations identified in the skeletal muscle actin gene; the identification of mutations in myosin causing hereditary inclusion body myopathy and hyaline body myopathy and the identification of mutations in myotilin in myofibrillar myopathy. SUMMARY: An increasing spectrum of human muscle diseases is being shown to be caused by mutations in proteins of all the major components of the sarcomere. Molecular analysis is providing a more accurate delineation of these diseases, but for the giant nebulin and titin genes, molecular diagnosis remains difficult. Treatment options for these disorders will only come through a deeper understanding of the sarcomere and of the pathogenesis of its disorders.

Actins↗
PubMed2004

Actin-related myopathy without any missense mutation in the ACTA1 gene.

Actinopathies are defined by missense mutations in the ACTA1 gene coding for sarcomeric actin, of which some 70 families have, so far, been identified. Often, but not always, muscle fibers carry large patches of actin filaments. Many such patients also have nemaline myopathy, qualifying actinopathies as a subgroup of nemaline myopathies. This article concerns a then newborn, now 2 1/2-year-old boy, the first and single child of nonconsanguineous parents, who was born floppy, requiring immediate postnatal assisted ventilation. A quadriceps muscle biopsy revealed large patches of thin myofilaments reacting at light and electron microscopic levels with antibodies against actin but only a few sarcoplasmic rods and no intranuclear rods. DNA analysis of the patient's and both parents' blood did not reveal any missense mutation in the ACTA1 gene. Thus, this congenital myopathy can be caused by a new type of ACTA1 gene mutation, a new non-ACTA1 gene mutation, or no mutation at all, designating it as an actin-related myopathy, perhaps a new type of congenital myopathy and a new member of protein aggregate myopathies marked by aggregation of proteins within muscle fibers, among them desminopathies, alpha-beta crystallinopathies, other desmin-related myopathies (also termed myofibrillar myopathies), actinopathies and, now, actin-related myopathies.

Actins↗
PubMed2003

New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.

Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have recently been shown to cause Ullrich congenital muscular dystrophy (UCMD), a frequently severe disorder characterized by congenital muscle weakness with joint contractures and coexisting distal joint hyperlaxity. Dominant mutations in all three collagen VI genes had previously been associated with the considerably milder Bethlem myopathy. Here we report that a de novo heterozygous deletion of the COL6A1 gene can also result in a severe phenotype of classical UCMD precluding ambulation. The internal gene deletion occurs near a minisatellite DNA sequence in intron 8 that removes 1.1 kb of genomic DNA encompassing exons 9 and 10. The resulting mutant chain contains a 33-amino acid deletion near the amino-terminus of the triple-helical domain but preserves a unique cysteine in the triple-helical domain important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism was our analysis of a patient with a much milder phenotype, in whom we identified a previously described Bethlem myopathy heterozygous in-frame deletion of 18 amino acids somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene. This deletion removes the crucial cysteine, so that dimer formation cannot occur and the abnormal molecule is not secreted, preventing the strong dominant negative effect. Our studies provide a biochemical insight into genotype-phenotype correlations in this group of disorders and establish that UCMD can be caused by dominantly acting mutations.

Amino Acid Sequence↗
PubMed2002

Sarcolemmal proteins and the spectrum of limb-girdle muscular dystrophies.

Proteins of the sarcolemma are of crucial importance for the pathogenesis of muscular dystrophies. This update focuses on the dystrophin-associated proteins including the dystroglycan and sarcoglycan complexes, caveolin-3, dysferlin, and the extracellular matrix component collagen type VI. The molecular findings are correlated with some of the clinical phenotypes that are part of the limb-girdle muscular dystrophy spectrum, including fukutin-related proteinopathy (LGMD 21), the sarcoglycanopathies (LGMD 2C-F), caveolinopathy (LGMD 1C), dysferlinopathy (LGMD 2B), and finally Bethlem myopathy. Although recent progress has been tremendous, much remains to be learned about the pathophysiological consequences caused by a deficiency of any one of these components.

Adolescent↗
PubMed2002

Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation.

Duchenne muscular dystrophy (DMD) is a severe progressive muscle-wasting disorder caused by mutations in the dystrophin gene. Studies have shown that bone marrow cells transplanted into lethally irradiated mdx mice, the mouse model of DMD, can become part of skeletal muscle myofibers. Whether human marrow cells also have this ability is unknown. Here we report the analysis of muscle biopsies from a DMD patient (DMD-BMT1) who received bone marrow transplantation at age 1 year for X-linked severe combined immune deficiency and who was diagnosed with DMD at age 12 years. Analysis of muscle biopsies from DMD-BMT1 revealed the presence of donor nuclei within a small number of muscle myofibers (0.5-0.9%). The majority of the myofibers produce a truncated, in-frame isoform of dystrophin lacking exons 44 and 45 (not wild-type). The presence of bone marrow-derived donor nuclei in the muscle of this patient documents the ability of exogenous human bone marrow cells to fuse into skeletal muscle and persist up to 13 years after transplantation.

Adolescent↗