Functions of fukutin, a gene responsible for Fukuyama type congenital muscular dystrophy, in neuromuscular system and other somatic organs.
Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disease, exhibiting muscular dystrophy, and central nervous system (CNS) and ocular malformations. It is included in alpha-dystroglycanopathy, a group of muscular dystrophy showing reduced glycosylation of alpha-dystroglycan. alpha-Dystroglycan is one of the components of dystrophin-glycoprotein complex linking extracellular and intracellular proteins. The sugar chains of alpha-dystroglycan are receptors for extracellular matrix proteins such as laminin. Fukutin, a gene responsible for FCMD, is presumably related to the glycosylation of alpha-dystroglycan like other causative genes of alpha-dystroglycanopathy. The CNS lesion of FCMD is characterized by cobblestone lissencephaly, associated with decreased glycosylation of alpha-dystroglycan in the glia limitans where the basement membrane is formed. Astrocytes whose endfeet form the glia limitans seem to be greatly involved in the genesis of the CNS lesion. Fukutin is probably necessary for astrocytic function. Other components of the CNS may also need fukutin, such as migration and synaptic function in neurons. However, roles of fukutin in oligodendroglia, microglia, leptomeninges and capillaries are unknown at present. Fukutin is expressed in various somatic organs as well, and appears to work differently between epithelial cells and astrocytes. In the molecular level, since the dystrophin-glycoprotein complex is linked to cell signaling pathways involving c-src and c-jun, fukutin may be able to affect cell proliferation/survival. Fukutin was localized in the nucleus on cancer cell lines. With the consideration that mutations of fukutin give rise to wide spectrum of the clinical phenotype, more unknown functions of fukutin besides the glycosylation of alpha-dystroglycan can be suggested. Trials for novel treatments including gene therapy are in progress in muscular dystrophies. Toward effective therapies with minimal side effects, precise evaluation of the pathomechanism of FCMD and the function of fukutin would be required.
Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan. sheto@research.twmu.ac.jp
Tomoko
T
Yamamoto
Noriyuki
N
Shibata
Yoshiaki
Y
Saito
Makiko
M
Osawa
Makio
M
Kobayashi
D000818:Animals; D002465:Cell Movement; D002490:Central Nervous System / Q000033:anatomy & histology / Q000473:pathology* / Q000503:physiopathology*; D002986:Clinical Trials as Topic; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D009206:Myocardium / Q000378:metabolism / Q000473:pathology
D016189:Dystrophin; C113587:FKTN protein, human; D006023:Glycoproteins; D008565:Membrane Proteins