Expression and localization of fukutin, POMGnT1, and POMT1 in the central nervous system: consideration for functions of fukutin

Abstract

Fukuyama-type congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS) are congenital muscular dystrophies associated with central nervous system (CNS) lesions, represented by cobblestone lissencephaly and eye anomalies. The glia limitans, formed by astrocytic endfeet and covered with the basement membrane, is disrupted in fetal cases of these diseases. A gene responsible for FCMD is fukutin and that for MEB is protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1). Mutations in protein-O-mannosyltransferase 1 (POMT1) have been found in some WWS cases. POMGnT1 and POMT1 are involved in glycosylation of alpha-dystroglycan, which is one of the components of dystrophin-glycoprotein complex, linking dystrophin and extracellular matrix proteins at the basement membrane. Fukutin seems to have similar functions to those of POMGnT1 and POMT1, but its functions still remain to be clarified. In situ hybridization reveals that fukutin, POMGnT1, and POMT1 are expressed especially in astrocytes. Decrease of glycosylated alpha-dystroglycan has been reported in the skeletal muscle of FCMD, MEB, and WWS. Moreover, decrease of fukutin and glycosylated alpha-dystroglycan is observed in the brain of FCMD cases. Because astrocytes are involved in basement membrane formation at the glia limitans, fukutin, POMGnT1, and POMT1 are considered to relate to the pathogenesis of CNS lesions, and fukutin may be related to glycosylation of alpha-dystroglycan. Fukutin, POMGnT1, and POMT1 are expressed in immature neurons, suggesting they are also involved in neuronal migration itself. POMGnT1 and POMT1 are expressed in many mature neurons, but fukutin is positive in a few mature neurons. FCMD is a rather mild disease among FCMD, MEB, and WWS, and POMGnT1 and POMT1 seems to have more critical roles compared to fukutin in mature neurons.

A developmental and genetic classification for malformations of cortical development: update 2012

“…This observation clarifies why periventricular nodular heterotopia is caused by ARFGEF1 mutations even though its protein product (BIG2) is not involved in neuronal migration (Ferland et al , 2009). Similar to subpial heterotopia in cobblestone malformations, which result from a loss of structural integrity of the pial limiting membrane (Yamamoto et al , 2004; Luo et al , 2011), the denuded ventricular epithelium in periventricular nodular heterotopia may cause disengagement of radial glia, resulting in an inability of young neurons to migrate away (Ferland et al , 2009). Neurons in periventricular nodular heterotopia seem to be arranged in a layered pattern (Garbelli et al , 2009); analysis of layer-specific genes suggests that the outer layer of neurons in the nodule is composed of layer 6 neurons (expressing Rorβ ), with the next layer being composed of layer 5 (expressing Er81 ) and the next for layer 4 (expressing Nurr1 ) (Garbelli et al , 2009).…”

Ectopia of meningeal fibroblasts and reactive gliosis in the cerebral cortex of the mouse model of muscle‐eye‐brain disease

“…POMGnT1 is expressed in astrocytes (Yamamoto et al, 2004). O-mannosylated glycans may be involved in the regulation of astroglial genesis such that, without proper mannosyl glycans, more GFAP-positive astrocytes are generated.…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…yamamoto et al 164 analysed the expression and localization of fukutin, PoMGnT1, and PoMT1 in the CNs and discussed the mechanism of lesions linked to these three glycosyltransferase whose changes are represented by migration disorders in FCMD, MeB, and WWs. They observed that fukutin, PoMGnT1, and PoMT1 are expressed especially in astrocytes that compose the astrocytic glia limitans and therefore is involved in the formation of the basement membrane.…”