Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development

Abstract

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal-recessive disorders in Japan, is characterized by congenital muscular dystrophy associated with brain malformation due to a defect during neuronal migration. Through positional cloning, we previously identified the gene for FCMD, which encodes the fukutin protein. Here we report that chimeric mice generated using embryonic stem cells targeted for both fukutin alleles develop severe muscular dystrophy, with the selective deficiency of alpha-dystroglycan and its laminin-binding activity. In addition, these mice showed laminar disorganization of the cortical structures in the brain with impaired laminin assembly, focal interhemispheric fusion, and hippocampal and cerebellar dysgenesis. Further, chimeric mice showed anomaly of the lens, loss of laminar structure in the retina, and retinal detachment. These results indicate that fukutin is necessary for the maintenance of muscle integrity, cortical histiogenesis, and normal ocular development and suggest the functional linkage between fukutin and alpha-dystroglycan.

Fukuyama‐type congenital muscular dystrophy (FCMD) and α‐dystroglycanopathy

“…Fukutin may be involved in the modification of lamininbinding carbohydrate residues in α-dystroglycan, and, in the absence of fukutin, the linkage between laminin and α-dystroglycan may never be established on the muscle cell surface. This cenario is also consistent with the report that chimeric mice lacking skeletal muscle dystroglycan [7] developed muscular dystrophy similar to the fukutin-deficient chimeric mice [30]. Finally, the role of dystroglycan in the pathogenesis of brain and eye defects in FCMD remains unclear.…”

“…These results indicate that fukutin is necessary for the maintenance of muscle integrity, cortical histiogenesis, and normal ocular development and suggest the functional linkage between fukutin and α-dystroglycan. These mice are suitable models for studying the molecular pathogenesis and therapeutic approaches of the complex disorders consisting of the simultaneous occurrence of central nervous, ocular, and muscular abnormalities [30].…”

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

“…To date, however, there has been no demonstration of enzymatic activity for this protein. Global loss of Fcmd in mice is lethal at an early embryonic stage, 53 and chimeric mice lacking this gene in a subset of cells demonstrate most facets of the cellular pathology found in FCMD. 53 FKRP was named on the basis of its sequence homology with fukutin.…”

“…Global loss of Fcmd in mice is lethal at an early embryonic stage, 53 and chimeric mice lacking this gene in a subset of cells demonstrate most facets of the cellular pathology found in FCMD. 53 FKRP was named on the basis of its sequence homology with fukutin. Like fukutin, FKRP has a domain structure and sequence that is indicative of a glycosyltransferase, but again the enzymatic activity is unknown.…”

Human genetic deficits in glycan formation.

“…57) Consistent with this finding, highly glycosylated α-dystroglycan was selectively deficient in the skeletal muscle of FCMD patients. 58) Recently, Takeda et al 59) generated chimeric mice using embryonic stem cells in which the fukutin gene was targeted for disruption. These mice developed severe muscular dystrophy, with a selective deficiency of α-dystroglycan and its laminin-binding activity.…”