The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

Function and genetics of dystrophin and dystrophin-related proteins in muscle

Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.

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Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Dystonias comprise a group of movement disorders that are characterized by involuntary movements and postures. Insight into the nature of neuronal dysfunction has been provided by the identification of genes responsible for primary dystonias, the characterization of animal models and functional evaluations and in vivo brain imaging of patients with dystonia. The data suggest that alterations in neuronal development and communication within the brain create a susceptible substratum for dystonia. Although there is no overt neurodegeneration in most forms of dystonia, there are functional and microstructural brain alterations. Dystonia offers a window into the mechanisms whereby subtle changes in neuronal function, particularly in sensorimotor circuits that are associated with motor learning and memory, can corrupt normal coordination and lead to a disabling motor disorder.

The pathophysiological basis of dystonias

The autism spectrum disorders (ASD) comprise a complex group of behaviorally related disorders that are primarily genetic in origin. Involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD has been suggested by the occurrence of ASD in patients with disorders arising from epigenetic mutations (fragile X syndrome) or that involve key epigenetic regulatory factors (Rett syndrome). Moreover, the most common recurrent cytogenetic abnormalities in ASD involve maternally derived duplications of the imprinted domain on chromosome 15q11-13. Thus, parent of origin effects on sharing and linkage to imprinted regions on chromosomes 15q and 7q suggest that these regions warrant specific examination from an epigenetic perspective, particularly because epigenetic modifications do not change the primary genomic sequence, allowing risk epialleles to evade detection using standard screening strategies. This review examines the potential role of epigenetic factors in the etiology of ASD.

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Epigenetics of autism spectrum disorders

Genomic imprinting in gametogenesis marks a subset of mammalian genes for parent-of-origin-dependent monoallelic expression in the offspring. Embryological and classical genetic experiments in mice that uncovered the existence of genomic imprinting nearly two decades ago produced abnormalities of growth or behavior, without severe developmental malformations. Since then, the identification and manipulation of individual imprinted genes has continued to suggest that the diverse products of these genes are largely devoted to controlling pre- and post-natal growth, as well as brain function and behavior. Here, we review this evidence, and link our discussion to a website (http://www.otago.ac.nz/IGC) containing a comprehensive database of imprinted genes. Ultimately, these data will answer the long-debated question of whether there is a coherent biological rationale for imprinting.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.10129

Physiological functions of imprinted genes.

The dystonias are a common clinically and genetically heterogeneous group of movement disorders More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs 11-13) Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 32 Mb SGCE is expressed in all brain regions examined Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene

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Tanja Müller

Papers

Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome.