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3683-3687-Dystroglycan Induced Muscular Dystrophies – a Review

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3683-3687-Dystroglycan Induced Muscular Dystrophies – a Review Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3683-3687 Dystroglycan induced muscular dystrophies – a review Q.-Z. ZHANG Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China Department of Neurology, The Fifth People’s Hospital of Jinan, Jinan, Shandong, China Abstract. – Dystroglycanopathies are mus - dystrophies caused predominantly by mutations cular dystrophies caused by mutations in genes in genes involved in the O-linked glycosylation involved the in O-linked glycosylation of -dys - 2 α of α-dystroglycan . troglycan. Severe forms of these conditions re - In addition to muscle dystrophy, a constella - sult in abnormalities in exhibit brain and ocular developmental too, in addition to muscular dys - tion of brain anomalies, ranging from mild cog - trophy. The full spectrum of developmental nitive impairment to severe mental retardation, pathology is caused mainly by loss of dystrogly - with or without structural malformations, is pre - can from Bergmann glia. Moreover, cognitive sented in these maladies; yet what role dystrogly - deficits are constant features of severe forms of can plays in the central nervous system remains dystroglycanopathies. However, the precise mol - largely undiscovered. Thus, understanding how ecular mechanism leading to neuronal dysfunc - tion in these diseases is not fully known yet. The the protein dystroglycan contributes to brain de - present review article will discuss the impor - velopment in general, and cerebellar histogenesis tance of dystroglycan in cerebellar development in particular, is imperative to elucidate the mech - and associated pathological states. anisms leadings to dystroglycanopathy-associat - ed cerebellar dysplasia. The present review shall Key Words: be focused on the above theme and will explore Dystroglycan, Cerebellar development, Dystrogly - all important associated areas. canpathies . Dystroglycanopathy and Congenital Muscular Dystrophy The common biochemical hallmark for these Introduction diseases is hypoglycosylation and reduced lig - 3 and-binding affinity of α-DG . These dystrophies Cobblestone lissencephaly belongs to a cate - present a broad clinical spectrum, ranging from gory of disorders characterized by structural mal - congenital muscular dystrophy (CMD) with brain formation of the brain, caused by defects in neu - and eye involvement in severe cases to limb-gir - ronal migration during early development 1. The dle muscular dystrophy (LGMD) in milder in - cobblestone phenotype is the result of neuroglial stances 4. CMD is a heterogeneous group of dis - over migration into the subarachnoid space, lead - eases with autosomal recessive inheritance, char - ing to the formation of an additional cortical lay - acterized by the onset of hypotonia, muscle er; the ramification is heterotopia that produces weakness, contractures at birth or within the first an unusually “bumpy ” brain surface. Clinical few months of life, and by dystrophic changes representations of this disorder include cortical visible in the muscle biopsy. The clinical diversi - dysplasia, dysmyelination, and pontocerebellar ty of CMD is shown by the different degrees of dysplasia. The presence of cobblestone delay in motor developmental, physical disabili - lissencephaly is pathognomonic of a group of ty, muscle pathology, and by presence or absence congenital muscular dystrophies: Walker-War - of mental retardation. burg syndrome, muscle-eye-brain disease, and Within the brain, dystroglycan is expressed in Fukuyama congenital muscular dystrophy. These astrocytic endfeet abutting the glia limitans and diseases are the severe manifestations of a het - the intracerebral vasculature 5. In addition to be - erogeneous group of autosomal recessive disor - ing localized at the inner limiting membrane ders termed “dystroglycanopathies ” – muscular and the basal laminae of blood vessels, DG is Corresponding Author: Qizhi Zhang, MD; e-mail: [email protected] 3683 Q.-Z. Zhang expressed by photoreceptor cells in the outer the protein component of the basal lamina plexiform layer of the retina 6. In addition to which surrounds muscle fibers, cause merosin- this , DG has been confirmed to be expressed deficient muscular dystrophy 14,15 . This corrobo - important brain parts including all major neu - rates the perception that any disruption to the rons and glia in the developing central nervous DGC-linked ECM and muscle fiber cytoskele - system 7. On the other hand, a study in recent ton, whether it be minimized expression of the past has confirmed its presence in the develop - protein component of the basement membrane, ing cerebellum, in granule cell precursors, Purk - or diminished ligand binding capability of DG, inje cells, radial glia, and Bergmann glia 8. Fur - or reduced expression of the DGC, is sufficient thermore , in the BM receptors, dystroglycan is to cause muscular dystrophy. present as dystrophin-glycoprotein Complex comprised of an extracellular -subunit and a Post-translational modification of 9 α transmembrane β-subunit . The physiological α-Dystroglycan studies about its functional evaluation con - Dystroglycan (DG) is a glycoprotein that un - firmed the involvement of DG in diverse cellu - dergoes glycosyltransferase -mediated N-glyco - lar functions like skeletal muscle membrane in - sylation, mucin-type O-glycosylation, O-man - tegrity maintenance, structural as well as func - nosylation, and an identified phosphorylated O- tional regulation of the CNS and skeletal mus - mannosyl glycan bearing xylose and glucuronic cle regulation 10,11 . Besides this, the precise func - acid-containing polysaccharide. Loss of N- tion of the DGC remains to be described, but it linked glycosylation on DG has no affect on its is suggested to bestow sarcolemmal stability ability to bind its ligand; however, loss of O- during muscle contraction. So, far it is now cer - linked glycosylation appears to disrupt DG-lig - tain that genetic causes of various reported mus - and binding 16 . As it happens, defects in O-man - cular dystrophies are associated with mutations nosyl glycan synthesis, caused by mutations in in various components of DGC . genes required for α-DG glycosylation, give In addition to DG and dystrophin, the core rise to congenital disorders termed dystrogly - proteins of the DGC in skeletal muscle are the canopathies. Biochemical analysis on skeletal sarcoglycans-sarcospan sub-complex, whose muscle biopsy from these patients revealed the purported function is to stabilize the whole hallmarks of dystroglycanopathy: hypoglycosy - DGC within the sarcolemma. Indeed, mutations lated α-DG, reduced expression of laminin α2, in either sarcoglycans or dystrophin reduce the and reduced laminin-binding capability, sug - expression or perturb the formation of the entire gesting a connection between CDG and dystro - DGC, and are thought to be one of the underly - glycanopathy. ing mechanisms responsible for their respective muscular dystrophies. Additional components Extracellular Interactions of Dystroglycan of the DGC include dystrobrevins and syn - Dystroglycan (DG) is ubiquitously expressed trophins, two types of dystrophin-binding pro - in a number of tissues and has, thus, been associ - teins that do not appear to have direct roles in ated with several proteins of multiple functions. the mechanical function of the DGC, but rather Notwithstanding the omnipresent distribution serve as docking sites for other intracellular sig - and the numerous binding partners, DG has been naling proteins 12 . Mutation in the dystroglycan studied most extensively in muscle, particularly gene (DAG1) itself or mutations in genes en - in relation to its role in the dystrophin-glycopro - coding known and putative glycosyltransferases tein complex and associated muscular dystro - – enzymes involved in the post-translational phies, while much less is known about its func - 17 modifications of α-DG – lead to a group of het - tions in the brain . This section will describe the erogeneous muscular dystrophies; these dystro - significance of DG-ligand interplays in the con - phies have a spectrum of clinical manifestations text of brain development and disease, focusing ranging from limb-girdle phenotypes to severe on extracellular interactions via the numerous brain and eye malformations and mental retar - glycans on -DG. The mucin domain of -DG is 13 α α dation . Hypoglycosylation of α-DG and ensu - in fact decorated with O-linked glycans, amongst ing reduced ligand binding affinity is the under - which the phosphorylated O-mannose polysac - lying mechanism leading to disease manifesta - charide was recently identified to be crucial for 18 tion. Meanwhile, mutations in the LAMA2 gene α-DG ’s ligand-binding affinity . α-DG binds to encoding the α2 subunit of laminin (merosin), laminin G (LG) domain-containing proteins in 3684 Dystroglycan induced muscular dystrophies – a review the extracellular space, including components of tor ribbon synapse 27 . In the visual system, pho - the basement membrane (BM) such as agrin, toreceptors detect and distinguish a wide range laminin, and perlecan, synaptic adhesion mole - of light intensities, then transmit the received cules α-neurexins and β-neurexins, pikachurin at light information to bipolar and horizontal cells the photoreceptor ribbon synapse, and slit at the in the retina using a special type of synapse spinal cord ventral midline 19-21 . Collectively, called ribbon synapse. The ribbon synapse en
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