Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson syndrome.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene, which encodes spermine synthase, and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human gene variants and disease presentations.

CRISPRa-induced upregulation of human compensates for -deficiency in Merosin-deficient congenital muscular dystrophy.

Merosin-deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder caused by mutations in the gene, resulting in a defective form of the extracellular matrix protein laminin-α2 (LAMA2). Individuals diagnosed with MDC1A exhibit progressive muscle wasting and declining neuromuscular functions. No treatments for this disorder are currently available.

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a novel mouse model of Snyder-Robinson Syndrome.

Polyamines (putrescine, spermidine, and spermine) are essential molecules for normal cellular functions and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to accumulation of spermidine in an X-linked recessive disorder known as Snyder-Robinson syndrome (SRS). Presently, no treatments exist for this rare disease that manifests with a spectrum of symptoms including intellectual disability, developmental delay, thin habitus, and low muscle tone.

A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene.

Neuromuscular disorders are often caused by heterogeneous mutations in large, structurally complex genes. Targeting compensatory modifier genes could be beneficial to improve disease phenotypes. Here we report a mutation-independent strategy to upregulate the expression of a disease-modifying gene associated with congenital muscular dystrophy type 1A (MDC1A) using the CRISPR activation system in mice.

Development of therapeutic genome engineering in laminin-α2-deficient congenital muscular dystrophy.

Muscular dystrophies are a heterogeneous group of genetic muscle diseases that are often characterized by pathological findings of muscle fiber degeneration and the replacement of muscle fibers with fibrotic/connective tissues. In spite of the genetic causes of many of these conditions having been identified, curative treatments are still lacking. Recently, genome engineering technologies, including targeted gene editing and gene regulation, have emerged as attractive therapeutic tools for a variety of muscular dystrophies.

Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease.

Gene-panel and whole-exome analyses are now standard methodologies for mutation detection in Mendelian disease. However, the diagnostic yield achieved is at best 50%, leaving the genetic basis for disease unsolved in many individuals. New approaches are thus needed to narrow the diagnostic gap.

Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism.

Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle.

Exon Snipping in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder caused by mutations in the DMD gene encoding dystrophin. We discuss very recent studies that used CRISPR/Cas9 technology to 'snip out' mutated exons in DMD, restoring the reading frame of the gene. We also present cautionary aspects of translating this exciting technology into clinical practice.

Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders.

Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals.

Targeting TGF-β Signaling by Antisense Oligonucleotide-mediated Knockdown of TGF-β Type I Receptor.

Duchenne muscular dystrophy (DMD) is caused by lack of functional dystrophin and results in progressive myofiber damage and degeneration. In addition, impaired muscle regeneration and fibrosis contribute to the progressive pathology of DMD. Importantly, transforming growth factor-β (TGF-β) is implicated in DMD pathology and is known to stimulate fibrosis and inhibit muscle regeneration.

Novel Ex Vivo Culture Method for the Study of Dupuytren's Disease: Effects of TGFβ Type 1 Receptor Modulation by Antisense Oligonucleotides.

Dupuytren's disease (DD) is a benign fibroproliferative disease of the hand. It is characterized by the excessive production of extracellular matrix (ECM) proteins, which form a strong fibrous tissue between the handpalm and fingers, permanently disrupting the fine movement ability. The major contractile element in DD is the myofibroblast (MFB).

Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G→A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP.

Cell-type specific regulation of myostatin signaling.

The transforming growth factor (TGF)-β family member myostatin is an important regulator of myoblast, adipocyte, and fibroblast growth and differentiation, but the signaling mechanisms remain to be established. We therefore determined the contribution of myostatin type I receptors activin receptor-like kinase-4 (ALK4) and -5 (ALK5) and different coreceptors in C2C12 myoblasts, C3H10T1/2 mesenchymal stem cells, and 3T3-L1 fibroblasts, as well as in primary myoblast and fibroblasts. We performed siRNA-mediated knockdown of each receptor and measured signaling activity using Smad3-dependent luciferase and Smad2 phosphorylation assays with nontargeting siRNA as control.

Dual exon skipping in myostatin and dystrophin for Duchenne muscular dystrophy.

Background: Myostatin is a potent muscle growth inhibitor that belongs to the Transforming Growth Factor-β (TGF-β) family. Mutations leading to non functional myostatin have been associated with hypermuscularity in several organisms. By contrast, Duchenne muscular dystrophy (DMD) is characterized by a loss of muscle fibers and impaired regeneration.

BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model.

Duchenne Muscular Dystrophy (DMD) is an X-linked lethal muscle wasting disease characterized by muscle fiber degeneration and necrosis. The progressive pathology of DMD can be explained by an insufficient regenerative response resulting in fibrosis and adipose tissue formation. BMPs are known to inhibit myogenic differentiation and in a previous study we found an increased expression of a BMP family member BMP4 in DMD myoblasts.

ATP8A1 activity and phosphatidylserine transbilayer movement.

The asymmetric distribution of the amino-containing phospholipids, phosphatidyl-serine (PS) and phosphatidyl-ethanolamine (PE), across the two leaflets of red blood cell (RBC) membrane is essential to the function and survival of the cell. PS and PE are sequestered in the inner leaflet by an ATP-dependent transport activity of a membrane protein known as the RBC flippase that specifically moves amino-phospholipids from the outer to the inner leaflet. The enucleated RBC lacks the means to replace damaged enzymes and inactivation of the flippase can lead to the unwarranted exposure of PS on the cell surface.