δ-Sarcoglycan-deficient muscular dystrophy: from discovery to therapeutic approaches

Mutations in the δ-sarcoglycan gene cause limb-girdle muscular dystrophy 2F (LGMD2F), an autosomal recessive disease that causes progressive weakness and wasting of the proximal limb muscles and often has cardiac involvement. Here we review the clinical implications of LGMD2F and discuss the current understanding of the putative mechanisms underlying its pathogenesis. Preclinical research has benefited enormously from various animal models of δ-sarcoglycan deficiency, which have helped researchers to explore therapeutic approaches for both muscular dystrophy and cardiomyopathy

Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9

OBJECTIVE: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities. METHODS: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain. RESULTS: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C \u3e A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C \u3e A compared with individuals heterozygous for c.826C \u3e A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C \u3e A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129). INTERPRETATION: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies

Untersuchungen zur Aquiferdynamik im Einzugsgebiet des Blautopfs (Oberjura, Süddeutschland)

Armbruster, V.; Selg, M.: Der Abfluss des Blautopfs im Spiegel der Grundwasserneubildung Bauer, M.; Selg, M.: Altersstruktur und Mittlere Verweilzeit im Grundwasser des Blautopfs und anderer Quellen und Brunnen im Oberjura-Karst Süddeutschlands Selg, M.; Schopper, M.; Straub, R.: Kurzzeitdynamik und Direktabfluss des Blautopf

Lower Limb Radiology of Distal Myopathy due to the S60F Myotilin Mutation

Distal myopathies are a clinically and genetically heterogenous group of disorders in which the distal limb musculature is selectively or disproportionately affected. Precisely defining specific categories is a challenge because of overlapping clinical phenotypes, making it difficult to decide which of the many known causative genes to screen in individual cases. In this study we define the distinguishing magnetic resonance imaging findings in myotilin myopathy by studying 8 genealogically unrelated cases due to the same point mutation in TTID. Proximally, the vastii, biceps femoris and semimembranosus were involved with sparing of gracilis and sartorius. Distally, soleus, gastrocnemius, tibialis anterior, extensor hallicus and extensor digitorum were involved. This pattern contrasts with other distal myopathies and provides further support for the role of imaging in the clinical investigation of muscle disease. Copyright (C) 2009 S. Karger AG, Base

The C-terminus of p63 contains multiple regulatory elements with different functions

The transcription factor p63 is expressed as at least six different isoforms, of which two have been assigned critical biological roles within ectodermal development and skin stem cell biology on the one hand and supervision of the genetic stability of oocytes on the other hand. These two isoforms contain a C-terminal inhibitory domain that negatively regulates their transcriptional activity. This inhibitory domain contains two individual components: one that uses an internal binding mechanism to interact with and mask the transactivation domain and one that is based on sumoylation. We have carried out an extensive alanine scanning study to identify critical regions within the inhibitory domain. These experiments show that a stretch of ~13 amino acids is crucial for the binding function. Further, investigation of transcriptional activity and the intracellular level of mutants that cannot be sumoylated suggests that sumoylation reduces the concentration of p63. We therefore propose that the inhibitory function of the C-terminal domain is in part due to direct inhibition of the transcriptional activity of the protein and in part due to indirect inhibition by controlling the concentration of p63. Keywords: p63, transcriptional regulation, auto-inhibition, sumoylatio

Potenziale eines gesellschaftlichen Dialogs zum Thema Bioökonomie

Eine biobasierte Wirtschaft kann bedeutend zur Erreichung globaler Nachhaltigkeit beitragen. Die Umsetzung muss aber sorgfältig begleitet werden, um Zielkonflikte konstruktiv zu lösen. Dazu bedarf es eines gesellschaftlichen Dialogs, der Fachleute und Bürger/innen in politische Prozesse einbezieht

Enzymatische Kohlenstoff-Kohlenstoff-Verknüpfungen

Für Dihydroxyacetonphosphat (DHAP) konnte eine einfache chemische Synthese entwickelt werden, die eine technische Anwendung von mit Kaninchenmuskel-Aldolase (RAMA) katalysierte Aldolreaktionen ermöglicht. So konnten u. a. auf diesem Wege die wichtigen Glycosidase-Inhibitoren 1-Desoxymannojirimycin (5) und 1-Desoxynojirimycin (6) in präparativen Mengen auf einfache Weise erhalten werden. Hefe-Transketolase (Hefe TK) wurde erganzend zu RAMA für stereoselektive C-C-Knüpfungen eingesetzt. Neben der Synthese der wichtigen Glycosidase-Inhibitoren 1, 4-Didesoxy-1,4-imino-D-arabinitol (12) und Fagomin (13) konnte darüber hinaus mittels Hefe TK-Katalyse ein neuer Zugang zu L-2-Hydroxyaldehyden erschlossen werden. Für präparative Anwendungen ist die neu aufgefundene Staphylococcus Carnosus-Aldolase (SCA) wegen ihrer größeren Stabilität und der einfacheren Zugänglichkeit als Katalysator für stereoselektive Aldolreaktionen besser geeignet als Kaninchenmuskel-Aldolase (RAMA)

Combined growth hormone and insulin-like growth factor 1 rescues growth retardation in glucocorticoid-treated mdx mice but does not prevent osteopenia

Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment. Hence, an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and therefore requires further exploration. A 5-week-old x-linked muscular dystrophy (mdx) mice were used as a model of DMD. They were treated with prednisolone ± GH + IGF-1 for 4 weeks and then compared to control mdx mice to allow the study of both growth and skeletal structure. GC reduced cortical bone area, bone fraction, tissue area and volume and cortical bone volume, as assessed by micro computed tomography (CT) In addition, GC caused somatic and skeletal growth retardation but improved grip strength. The addition of GH + IGF-1 therapy rescued the somatic growth retardation and induced additional improvements in grip strength (16.9% increase, P  < 0.05 compared to control). There was no improvement in bone microarchitecture (assessed by micro-CT and static histomorphometry) or biomechanical properties (assessed by three-point bending). Serum bone turnover markers (Serum procollagen 1 intact N-terminal propeptide (P1NP), alpha C-terminal telopeptide (αCTX)) also remained unaffected. Further work is needed to maximise these gains before proceeding to clinical trials in boys with DMD