Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.
OBJECTIVE
The fukutin gene (FKTN) is the causative gene for Fukuyama-type congenital muscular dystrophy, characterized by rather homogeneous clinical features of severe muscle wasting and hypotonia from early infancy with mental retardation. In contrast with the severe dystrophic involvement of skeletal muscle, cardiac insufficiency is quite rare. Fukuyama-type congenital muscular dystrophy is one of the disorders associated with glycosylation defects of alpha-dystroglycan, an indispensable molecule for intra-extra cell membrane linkage.


METHODS
Protein and functional analyses of alpha-dystroglycan and mutation screening of FKTN and other associated genes were performed.


RESULTS
Surprisingly, we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation. One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old. Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability. One cardiac muscle that underwent biopsy showed altered glycosylation of alpha-dystroglycan similar to that observed in a Fukuyama-type congenital muscular dystrophy patient.


CONCLUSIONS
FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy.
Murakami
Terumi
T
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo.|Department of Pediatrics, Tokyo Women's Medical University, Tokyo.
Hayashi
Yukiko K
YK
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo.
Noguchi
Satoru
S
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo.|Department of Pediatrics, Tokyo Women's Medical University, Tokyo.
Ogawa
Megumu
M
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo.
Nonaka
Ikuya
I
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo.
Tanabe
Yuzo
Y
Division of Neurology, Chiba Children's Hospital, Chiba.
Ogino
Mieko
M
Department of Neurology, Kitasato University School of Medicine, Kanagawa, Japan.
Takada
Fumio
F
Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan.
Eriguchi
Makoto
M
Division of Neurology, Saga University Faculty of Medicine, Saga, Japan.
Kotooka
Norihiko
N
Division of Cardiovascular Medicine, Saga University Faculty of Medicine, Saga, Japan.
Campbell
Kevin P
KP
Howard Hughes Medical Institute Research Laboratories, University of Iowa College of Medicine, Iowa City, IA.
Osawa
Makiko
M
Department of Pediatrics, Tokyo Women's Medical University, Tokyo.
Nishino
Ichizo
I
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo.
D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D018450:Disease Progression; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D018908:Muscle Weakness / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017354:Point Mutation / Q000235:genetics*; D012720:Severity of Illness Index
C113587:FKTN protein, human; D008565:Membrane Proteins; D049030:Dystroglycans