Congenital and yield two glycoproteins after post-translational modification:

Congenital muscular dystrophies (CMDs) are a group of heterogenous disorders, inherited in an autosomal recessive mode and characterised by muscles weakness, wasting and hypotonia and in some cases severe CNS involvement. CMDs present at birth or early childhood and become severe over time. A number of genes has been identified to be responsible for CMDs such as POMT1, POMT2, ISPD, FKTN, FKRP, and LARGE1. Defects in these genes affect post translational processing of a-dystroglycan ( extracellular matrix receptor) or molecules that involve in the extracellular matrix such as  laminin-?2 and collagen type VI. Dystrophin-glycoprotein complex (DGC) involve in the structural stability of the sarcolemma during contraction by linking cytoskeletal actin through dystrophin to the extracellular matrix ,mostly to laminin-2. This linkage is mediated by the dystroglycan and sarcoglycan subcomplexes. Dystroglycan is a polypeptide encoded by DAG1 gene, located on chromosome 3p21.31, and yield two glycoproteins after post-translational modification: a- and b-dystroglycan. B-dystroglycan protein binds intracellularly to dystrophin, utrophin, actin and Grb2 which is ERK-MAP kinase cascade’ components and rapsyn which has a role in the clustering of acetylcholine receptor. While ?-dystroglycan contains a mucin-like domain due to o-mannosyl–linked glycosylation and binds extracellularly to laminin-a2, perlecan, biglycan, neurexin and agrin in a ca+2-dependent manner. The primary function of ?-dystroglycan is to anchor cytoskeleton to extracellular matrix. This function stabilizes and protects muscle fibers in skeletal muscle while it directs the migration of neuroblasts in the brain during early development. Dystroglycan involves in several cellular processes such as development, cell adhesion, and signaling in muscle and non-muscle tissues, and also participate in the formation of basement membrane and linking the extracellular matrix to intracellular cytoskeleton which highly dependant on the glycosylation of a-dystroglycan and its ability to bind laminin-a2. Reduced glycosylation due to interference in glycosyltransferases activity or proteins that modify ?-dystroglycan, affect binding to the extracellular ligands resulting in conditions collectively known as dystroglycanopathies (asubtype of CMD), including Fukuyama congenital muscular dystrophy, muscle-eye-brain disease, Walker-Warburg syndrome,  Congenital MD Type 1C, and MDC1D.Fukuyama congenital muscular dystrophy (rare in western countries and exclusive in japan) affects skeletal muscle, brain, and eyes. Early infancy symptoms include hypotonia, facial muscle weakness which leads to ptosis and open mouth, weak cry, and poor feeding. During childhood, symptoms include joint deformities in addition to muscle weakness. Also, limit movement, impede motor skills development. FCMD also leads to abnormal brain development which can be seen in the form of polymicrogyria, pachygyria, agyria, and type II lissencephaly in addition to unusual neural migration. In microscopic study, the cerebral cortex of FCMD Fetuses brains appear to be covered by thick neurogliomesenchymal tissue that contains a combination of over-migrated neuronal and glial tissue and few Cajal-Retzius cells, subpial granular layer cells and glial cells which are deeply located. Over migrated neurogli element causes a breach in glia limitans which can be detected in the frontal, temporal, parietal lobes and rarely in the occipital cortex. In the cerebellum, there was a disruption in the continuity of the outer layer of granular cells leading to formation of cluster in subpial layer. Also the study found in some cases an abnormally phosphorylated tau (different from that found in Alzheimer’ disease) aggregated just above the neurogliomesenchymal tissue.The gene responsible for fukuyama congenital muscular dystrophy is FKTN, located on chromosome 9q31.2. The protein produce from this gene, fukutin , modify a-dystroglycan. Mutation in FKTN leads to a reduction in the amount fukutin produced. Consequently, the modification process of a-distoglycan is disrupted as well as its function. Defective a-dystroglycan will also lead to abnormal neural migration. Muscle eye brain disease present at birth with muscle weakness, hypotonia. Brain imaging of affected children shows signs of lissencephaly type II and pontocerebellar hypoplasia. Ocular malformation (myopia and glaucoma), retinal hypoplasia optic disc abnormalities can also be present. Individual with MEB seems to have distinct facial features such as large head and a flat mid-face. The gene responsible for muscle eye brain disease is POMGNT1 (protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-) ) , located in chromosome 1p34.1. This gene encode type II transmembrane protein located in Golgi apparatus and involve in O-mannosyl glycosylation. It has been suggested that this gene may participate in the synthesis of GlcNAc(beta1-2) Man(alpha1-) O-Ser/Thr moiety on alpha-dystroglycan. Mutation in other genes such as FKRP and POMT1 and 2 can also cause muscle eye brain disease. Walker-Warburg syndrome is the severest form of congenital muscular dystrophies that affect muscles, brain, and eyes. Brain abnormalities include lissencephaly type II, pontocerebellar hypoplasia (progressive atrophy of pon and cerebellum), in some cases hydrocephalus (fluid accumulation in the brain),  Meningoceles ( sac filled with spinal fluid and lack  neural tissue protrude from the spinal column) and  encephaloceles (sac protruding from the brain). Abnormal neuronal migration into subarachnoid space  leads to hemispheric fusion. Eye abnormalities include microphthalmia (abnormally small eyes with anatomic malformations), glaucoma (optic nerve damage due to the pressure of fluid accumulated inside the eye), severe retinal dysplasia (folds of retinal tissues), anterior chamber malformations, and cataracts (clouding of the lens).WWS is caused by mutation in several genes including POMT2, FCMD or FKRP. Mutation in POMT1  had been detected in 20% of WWS cases. POMT1 located on chromosome 9q34.13 and encode glycosyltransferase protein O-mannosyltransferse 1. This protein modify a-dystroglycan by adding mannose Merosin-deficient CMD or laminin a2 chain-deficient CMD appears as severe early-onset or mild late-onset.  Early onset manifest at birth or first few months. Affected infants suffer from severe muscle weakness, reduce muscle tone, weak spontaneous movement,  and joint contractures. Muscle weakness in the throat and face causes feeding difficulty which affects the quality of life and eventually affected children fail to thrive. Hypotonia affects the diaphragm (the muscle used for breathing) which leads to weak cry and breathing issue, and that may result in life-threatening conditions such as lung infections. Over time affected children suffer from scoliosis and lordosis and cannot ambulate without assistance. Speech difficulty may occur due to the weakness in facial and tongue muscle. However, intelligence remains intact. Due to these issues affected children may not survive past they adolescence.  Late-onset symptoms manifest later in childhood or adulthood. Muscle affected are shoulders, upper arms, pelvic area, and thighs. Affected children appear to have delayed motor development, back rigidity, joint contractures, scoliosis, breathing issues. However, can ambulate without assistance, and intelligence is not affected. Laminin-?2 deficiency related CMD prevalence estimated at 1/30000, and nearly one-third of CMD cases have a laminin-?2 deficiency which is a result of a mutation in the LAMA2 gene,   located on chromosome 6q22.33. This mutation occurs during post-translational proteolytic cleavage of laminin G-domain which will decrease the ability of laminin-a2 binding to a-dystroglycan.Laminin-2 is a heterotrimers that consist of three subunits chain ? ,? and ? which can bind using their central coiled-coiled domains. It is located in a complex network of proteins and molecule that are formed in the extracellular matrix and involved in cell growth regulation, cell motility and adhesion as well as formation and organisation of basement membranes.  Collagen VI is a form of collagen present in the extracellular matrices of muscle, skin, tendon, and vessels. The structure of collagen VI consist of three a- chain, each of these chain encoded by different gene. ?1(VI) encoded by COL6A1, ?2(VI) encoded by COL6A2  and both are located on chromosome 21q22, while ?3(VI) encoded by COL6A3 and located on chromosome 2q37. Mutation in these genes causes conditions known as collagen VI-related myopathies including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). It has been suggested that collagen VI involves in cell adhesion, proliferation, stimulation of DNA synthesis of mesenchymal cells and neural crest cell migration. Assembly of collagen VI is a complex process in which the three alpha chain associate to form a triple helical heterotrimeric monomer.After that, the monomer form a  dimer linked by disulfide bridge via aligning in an antiparallel staggered manner followed by alining laterally to form tetramer that are then secreted into the extracellular matrix. The end of each tetramer associate with other tetramers’ end to form double-beaded collagen VI microfibrils. Mutation in any of these genes disrupt the structures of their corresponding a-chain. These mutation can either alter a-chain but can incorporate with other chain, however the structure and function will be disrupted or can not incorporate completely, leading to collagen VI deficiency. Individuals with UCMD presents at birth with muscle weakness, hypotonia, distal joint hyperextensibility, joint contractures , skeletal deformities, hip dislocations and torticollis, signs of congenital pes adductus, prominent calcaneus. affected children are not able to walk without assistance due to a delay in motor milestone.


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