[Molecular pathomechanism of distal myopathy with rimmed vacuoles].
Distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (HIBM) are genetically identical autosomal recessive muscle disorders caused by mutations in the GNE gene. This gene encodes a bifunctional protein with UDP-GlcNAc 2-epimerase and ManNAc kinase activities that catalyze the rate limiting step and the succeeding step, respectively, in the sialic acid biosynthetic pathway. V572L mutation is the most prevalent among Japanese DMRV patients and accounts for about 60% of mutant alleles. Clinical spectrum of DMRV/HIBM seems to be wider than previously thought in terms of both the severity of the disease and the range of affected organs. There are rare asymptomatic homozygotes with missense GNE mutations, indicating the presence of mitigating factors. Surprisingly, more than 10% of the patients had a variety of cardiac abnormalities, suggesting that skeletal muscle may not be the only organ involved. Studies on recombinant GNE demonstrate a loss-of-function nature of the missense mutations identified. Patients' cells show decreased sialylation status which can be recovered by adding GNE metabolites, such as ManNAc and NeuAc. This indicates the possibility of developing a therapy for DMRV/HIBM by giving these metabolites to patients although we have to await the model mice that are currently being produced at several laboratories.
Nishino
Ichizo
I
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP).
Noguchi
Satoru
S
Murayama
Kumiko
K
Ohkuma
Aya
A
Kasahata
Naoki
N
Malicdan
May Christine V
MC
Hayashi
Yukiko K
YK
Nonaka
Ikuya
I
D002238:Carbohydrate Epimerases / Q000235:genetics; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D009132:Muscles / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D014617:Vacuoles / Q000235:genetics* / Q000648:ultrastructure
D002238:Carbohydrate Epimerases; C100033:UDP acetylglucosamine-2-epimerase