Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J.
OBJECTIVE
To determine the phenotype variability associated with the specific C-terminal M-line titin mutation known to cause autosomal dominant distal myopathy, tibial muscular dystrophy (TMD; MIM 600334), and limb girdle muscular dystrophy 2J (LGMD2J).


METHODS
Three hundred eighty-six individuals were genotyped for the Finnish founder mutation in titin (FINmaj) causing TMD/LGMD2J.


RESULTS
Two hundred seven patients were heterozygous for the mutation. Among these patients, 189 (91%) had a more common phenotype compatible with the classic description of TMD. However, 18 (9%) had unusual phenotypes such as proximal leg or posterior lower leg muscle weakness and atrophy even at onset. Four patients were confirmed homozygotes representing the LGMD2J phenotype. These homozygotes were half of the eight LGMD patients previously described in the original large consanguineous kindred.


CONCLUSIONS
Large variability of phenotypic expression caused by just one mutation, the Finnish FINmaj, suggests that no certain phenotype of myopathy/dystrophy can be excluded from being caused by mutated titin. Yet unknown homozygous or compound heterozygous titin mutations without phenotype in the heterozygote carriers may be responsible for undetermined recessive MD and LGMD.
Udd
B
B
Neurological Department, Vaasa Central Hospital, Finland. Bjarne.Udd@vshp.fi
Vihola
A
A
Sarparanta
J
J
Richard
I
I
Hackman
P
P
D017668:Age of Onset; D001284:Atrophy; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D064211:Connectin; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005387:Finland / Q000453:epidemiology; D005799:Genes, Dominant; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology; D018908:Muscle Weakness / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011494:Protein Kinases / Q000235:genetics* / Q000502:physiology
D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases