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C.I.2 Defective glycosylation in congenital muscular dystrophies: From glycobiology to α-dystroglycanopathies
Neuromuscular Disorders 20 (2010) 596–680
Contents lists available at ScienceDirect
Neuromuscular Disorders journal homepage: www.elsevier.com/locate/nmd
Abstracts (Please note that the underlining indicates the presenting author) CONGENITAL MUSCULAR DYSTROPHIES (CELEBRATING THE 50TH ANNIVERSARY OF FUKUYAMA CONGENITAL MUSCULAR DYSTROPHY) 1; INVITED LECTURES C.I.1 Fukuyama congenital muscular dystrophy – An overview Y. Fukuyama Tokyo Women’s Medical University, Department of Pediatrics, Tokyo, Japan Fukuyama congenital muscular dystrophy (FCMD) is a unique autosomal recessively inherited condition characterized by a combination of systemic progressive muscular dystrophy (PMD), severe cerebro-cerebellar cortical malformation in association with/without retinal derangement of very early onset. FCMD is the second most prevalent type of PMD in Japan, while it is extremely rare outside Japan. Historically, the first half of the 20th century was a dark age in terms of CMD. The category of CMD was practically absent in most international classifications of PMD until 1986, when MIM (McKusick) first enlisted FCMD as a disease entity. In the midst of this dark age, that is, in 1960, we first reported a series of 15 cases of CMD and advocated that this will represent a completely new disease entity. Key clues to the correct diagnosis were derived from keen clinical observation, application of then newly developed diagnostic procedures, including muscle biopsy, needle EMG and determination of serum CK activities. Another important factor was an exhaustive review of pertinent literatures. Clinical features of typical FCMD patients mimick those of the floppy infant syndrome of infancy and later, after age 2, resemble those of congenital multiple arthrogryposis. Life expectancy is shorter than that of Duchenne patients, but they can survive up to age 20 or more, not rarely. Recent molecular genetic studies revealed a certain degree of genotype–phenotype correlation among FCMD patients; in addition, the latest studies revealed that fukutin gene mutation have a far broader clinical spectrum than thought before, ranging from the WWS phenotype to the mildest LGMD2I. FCMD and fukutinopathy is no more a synonym. doi:10.1016/j.nmd.2010.07.006
C.I.2 Defective glycosylation in congenital muscular dystrophies: From glycobiology to a-dystroglycanopathies T. Endo Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan
doi:10.1016/j.nmd.2010.07.005
Glycosylation is the most common post-translational modification of proteins. The protein sequence data suggested that more than half of all proteins produced in mammalian cells are glycoproteins. Glycans of secreted glycoproteins affect many protein properties such as solubility, stability, protease sensitivity, and polarity, while glycans on cell surface glycoproteins are involved in various cellular functions including cell– cell and cell–matrix interactions during embryogenesis, immune reactions, and tumor development. The past decade of research on glycan function has revealed the etiology of a growing number of human genetic diseases with aberrant glycan formation. a-Dystroglycan (aDG) is a highly glycosylated surface membrane protein, plays an important role in muscle and brain development. The main glycan of a-DG was found to be O-mannosylglycan. We identified and characterized two glycosyltransferases involved in the biosynthesis of O-mannosylglycans. These two enzymes are responsible for congenital muscular dystrophies, muscle–eye–brain disease (MEB) and Walker–Warburg syndrome (WWS). In addition, defects in glycosylation of a-DG cause several forms of autosomal recessive muscular dystrophy, also called a-dystroglycanopathies, e.g., Fukuyama-type congenital muscular dystrophy (FCMD), congenital muscular dystrophy type 1C (MDC1C), limb-girdle muscular dystrophy 2I (LGMD2I), and congenital muscular dystrophy type 1D (MDC1D) since highly glycosylated a-DG was also found to be selectively deficient in the skeletal muscle of these patients. I will focus on the relation between aberrant glycosylation of a-DG and congenital muscular dystrophies. doi:10.1016/j.nmd.2010.07.007
C.I.3 Overview of congenital muscular dystrophies H. Topaloglu Hacettepe Children’s Hospital, Ankara, Turkey The congenital muscular dystrophies (CMD) are a quite diverse group of disorders. Currently, more than 15 genes are known to cause CMD, and the resulting disorders can be broadly divided into three groups. The largest group results from mutations in genes encoding structural proteins. The commonest form, merosin deficient CMD, results from mutations in LAMA2, encoding the laminin-a2 chain of laminin-2 (merosin), a key component of the muscle cell basement membrane. Another common condition, Ullrich syndrome, results from mutations in the collagen VI chain genes, COL6A1, COL6A2 or COL6A3, which comprise the extracellular matrix protein, collagen VI. CMD patients who present with moderate to severe mental
Contents lists available at ScienceDirect
Neuromuscular Disorders journal homepage: www.elsevier.com/locate/nmd
Abstracts (Please note that the underlining indicates the presenting author) CONGENITAL MUSCULAR DYSTROPHIES (CELEBRATING THE 50TH ANNIVERSARY OF FUKUYAMA CONGENITAL MUSCULAR DYSTROPHY) 1; INVITED LECTURES C.I.1 Fukuyama congenital muscular dystrophy – An overview Y. Fukuyama Tokyo Women’s Medical University, Department of Pediatrics, Tokyo, Japan Fukuyama congenital muscular dystrophy (FCMD) is a unique autosomal recessively inherited condition characterized by a combination of systemic progressive muscular dystrophy (PMD), severe cerebro-cerebellar cortical malformation in association with/without retinal derangement of very early onset. FCMD is the second most prevalent type of PMD in Japan, while it is extremely rare outside Japan. Historically, the first half of the 20th century was a dark age in terms of CMD. The category of CMD was practically absent in most international classifications of PMD until 1986, when MIM (McKusick) first enlisted FCMD as a disease entity. In the midst of this dark age, that is, in 1960, we first reported a series of 15 cases of CMD and advocated that this will represent a completely new disease entity. Key clues to the correct diagnosis were derived from keen clinical observation, application of then newly developed diagnostic procedures, including muscle biopsy, needle EMG and determination of serum CK activities. Another important factor was an exhaustive review of pertinent literatures. Clinical features of typical FCMD patients mimick those of the floppy infant syndrome of infancy and later, after age 2, resemble those of congenital multiple arthrogryposis. Life expectancy is shorter than that of Duchenne patients, but they can survive up to age 20 or more, not rarely. Recent molecular genetic studies revealed a certain degree of genotype–phenotype correlation among FCMD patients; in addition, the latest studies revealed that fukutin gene mutation have a far broader clinical spectrum than thought before, ranging from the WWS phenotype to the mildest LGMD2I. FCMD and fukutinopathy is no more a synonym. doi:10.1016/j.nmd.2010.07.006
C.I.2 Defective glycosylation in congenital muscular dystrophies: From glycobiology to a-dystroglycanopathies T. Endo Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan
doi:10.1016/j.nmd.2010.07.005
Glycosylation is the most common post-translational modification of proteins. The protein sequence data suggested that more than half of all proteins produced in mammalian cells are glycoproteins. Glycans of secreted glycoproteins affect many protein properties such as solubility, stability, protease sensitivity, and polarity, while glycans on cell surface glycoproteins are involved in various cellular functions including cell– cell and cell–matrix interactions during embryogenesis, immune reactions, and tumor development. The past decade of research on glycan function has revealed the etiology of a growing number of human genetic diseases with aberrant glycan formation. a-Dystroglycan (aDG) is a highly glycosylated surface membrane protein, plays an important role in muscle and brain development. The main glycan of a-DG was found to be O-mannosylglycan. We identified and characterized two glycosyltransferases involved in the biosynthesis of O-mannosylglycans. These two enzymes are responsible for congenital muscular dystrophies, muscle–eye–brain disease (MEB) and Walker–Warburg syndrome (WWS). In addition, defects in glycosylation of a-DG cause several forms of autosomal recessive muscular dystrophy, also called a-dystroglycanopathies, e.g., Fukuyama-type congenital muscular dystrophy (FCMD), congenital muscular dystrophy type 1C (MDC1C), limb-girdle muscular dystrophy 2I (LGMD2I), and congenital muscular dystrophy type 1D (MDC1D) since highly glycosylated a-DG was also found to be selectively deficient in the skeletal muscle of these patients. I will focus on the relation between aberrant glycosylation of a-DG and congenital muscular dystrophies. doi:10.1016/j.nmd.2010.07.007
C.I.3 Overview of congenital muscular dystrophies H. Topaloglu Hacettepe Children’s Hospital, Ankara, Turkey The congenital muscular dystrophies (CMD) are a quite diverse group of disorders. Currently, more than 15 genes are known to cause CMD, and the resulting disorders can be broadly divided into three groups. The largest group results from mutations in genes encoding structural proteins. The commonest form, merosin deficient CMD, results from mutations in LAMA2, encoding the laminin-a2 chain of laminin-2 (merosin), a key component of the muscle cell basement membrane. Another common condition, Ullrich syndrome, results from mutations in the collagen VI chain genes, COL6A1, COL6A2 or COL6A3, which comprise the extracellular matrix protein, collagen VI. CMD patients who present with moderate to severe mental