The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.During muscle differentiation, a specific program of gene expression leads to the translation of myofibrillar proteins and their assembly into contractile units, the sarcomeres, which are constantly remodeled to adapt to changes in mechanical load. The giant protein titin (also known as connectin) acts as a molecular blueprint for sarcomere assembly by providing specific attachment sites for numerous sarcomeric proteins, as well as acting as a molecular spring (1, 2). Titin also contains a catalytic serine-threonine kinase domain (TK), which is inhibited by a specific dual mechanism (3). However, the upstream elements controlling TK activation, its range of cellular substrates, and particularly the role of TK in mature muscle are largely unknown. Spanning half sarcomeres from Z disk to M band, titin is in a unique position to sense mechanical strain along the sarcomere (1). The elastic properties of the titin molecule and the mechanical deformation of the M band during stretch and contraction (4) suggest that the signaling properties of TK might be modulated by mechanically induced conformational changes. Molecular dynamics simulations suggest that mechanical strain can induce a catalytically active conformation of TK (5).The catalytic kinase domain of titin interacts with nbr1. We searched for further elements of a putative signaling pathway that might recognize mechanically induced conformational intermediates of titin's catalytic domain. In a systematic two-hybrid screening approach with various structure-based open states of the catalytic site [kin1, kin2, and kin3 (6)], we identified the zinc-finger protein nbr1 (7) as a TK ligand, which interacted via its Nterminal PB1 domain with the semiopened construct kin3 (Fig. 1, A and B). This interaction was also seen in precipitation experiments with nbr1 and TK-kin3 ( fig. S1A). Kin1, where the complete regulatory domain closes the active site, and kin2, where the a helix R1 (3) is deleted, did not interact. Thus, aR1 was necessary but not sufficient for nbr1 binding, which also required a semiopened catalyt-

Over the past decade there have been major advances in defining the genetic basis of the majority of congenital myopathy subtypes. However the relationship between each congenital myopathy, defined on histological grounds, and the genetic cause is complex. Many of the congenital myopathies are due to mutations in more than one gene, and mutations in the same gene can cause different muscle pathologies. The International Standard of Care Committee for Congenital Myopathies performed a literature review and consulted a group of experts in the field to develop a summary of (1) the key features common to all forms of congenital myopathy and (2) the specific features that help to discriminate between the different genetic subtypes. The consensus statement was refined by two rounds of on-line survey, and a three-day workshop. This consensus statement provides guidelines to the physician assessing the infant or child with hypotonia and weakness. We summarise the clinical features that are most suggestive of a congenital myopathy, the major differential diagnoses and the features on clinical examination, investigations, muscle pathology and muscle imaging that are suggestive of a specific genetic diagnosis to assist in prioritisation of genetic testing of known genes. As next generation sequencing becomes increasingly used as a diagnostic tool in clinical practise, these guidelines will assist in determining which sequence variations are likely to be pathogenic.

Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee.