A Myotonic Dystrophy Type I patient with Predominant Proximal Muscle Weakness without Action Myotonia- A Case Report and Review of Pathology.

PURPOSE: Early distal muscle weakness and myotonia are typical clinical presentations in type I myotonic dystrophy (DM1). We present a DM1 case with unusual predominant proximal weakness without action myotonia. CASE REPORT: The chief complaint of this 48-year-old female was difficulty in raising her arms and frequent falling in recent years. On neurological examination, proximal muscle weakness was more pronounced than the distal muscle groups, in addition to facial involvement. Although she did not experience any action myotonia throughout her life, hand and tongue myotonia were readily inducible by percussion during neurological examination. The diagnosis of DM1 was later supported by electromyography and neuropathological studies, and confirmed by molecular testing. The pathological findings in this patient and the characteristic features in typical DM1 patients were briefly reviewed. CONCLUSION: The unusual presentation of this DM1 patient suggests the importance of comprehensive neurological examination including percussion of thenar and tongue muscles, even in a patient with atypical distribution of muscle weakness and without a clear personal and family history of myotonia. In addition to molecular testing, muscle biopsy remains supportive in making the diagnosis.

Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection.

Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus (DEPN) which has been recognized as an epileptogenic zone. We generated a forebrain-specific Ctgf knockout (FbCtgf KO) mouse line in which the expression of Ctgf in the DEPN is eliminated. In this study, we adopted a pentylenetetrazole (PTZ)-induced seizure model and found similar severity and latencies to death between FbCtgf KO and WT mice. Interestingly, there was a delay in the seizure reactions in the mutant mice. We further observed reduced c-fos expression subsequent to PTZ treatment in the KO mice, especially in the hippocampus. While the densities of astrocytes and microglia in the hippocampus were kept constant after acute PTZ treatment, microglial morphology was different between genotypes. Our present study demonstrated that in the FbCtgf KO mice, PTZ failed to increase neuronal activity and microglial response in the hippocampus. Our results suggested that inhibition of Ctgf function may have a therapeutic potential in preventing the pathophysiology of epilepsy.

Prediction of clustered RNA-binding protein motif sites in the mammalian genome.

Sequence-specific interactions of RNA-binding proteins (RBPs) with their target transcripts are essential for post-transcriptional gene expression regulation in mammals. However, accurate prediction of RBP motif sites has been difficult because many RBPs recognize short and degenerate sequences. Here we describe a hidden Markov model (HMM)-based algorithm mCarts to predict clustered functional RBP-binding sites by effectively integrating the number and spacing of individual motif sites, their accessibility in local RNA secondary structures and cross-species conservation. This algorithm learns and quantifies rules of these features, taking advantage of a large number of in vivo RBP-binding sites obtained from cross-linking and immunoprecipitation data. We applied this algorithm to study two representative RBP families, Nova and Mbnl, which regulate tissue-specific alternative splicing through interacting with clustered YCAY and YGCY elements, respectively, and predicted their binding sites in the mouse transcriptome. Despite the low information content in individual motif elements, our algorithm made specific predictions for successful experimental validation. Analysis of predicted sites also revealed cases of extensive and distal RBP-binding sites important for splicing regulation. This algorithm can be readily applied to other RBPs to infer their RNA-regulatory networks. The software is freely available at http://zhanglab.c2b2.columbia.edu/index.php/MCarts.