The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis.
BACKGROUND
Distal myopathies (MPDs) are genetically heterogeneous. Genetic causes within this subgroup of muscle disorders remain largely unknown. An MPD linked to chromosome 14q11-q13 (MPD1) is rare, and to our knowledge, only one family with definitive linkage has been described.


OBJECTIVE
To describe the results of clinical and genetic analysis of the second kindred with MPD1.


METHODS
We have identified a family with an MPD segregating in an autosomal dominant fashion. We tested linkage to previously identified genetic loci on chromosomes 2p, 2q, and 14q. The coding sequence of PABP2 (the polyadenylate-binding protein 2 gene) was analyzed.


RESULTS
Every affected individual had selective weakness of foot extensors, with the average age of symptom onset at 20 years. Some patients also had proximal weakness, but none had signs of finger or hand extensor muscle involvement, even in advanced stages of the disease. Two typically affected individuals had signs of idiopathic dilated cardiomyopathy. Genetic analysis detected a tight linkage to chromosome 14q11-q13. Recombination at the telomeric end of the 14q11-q13 locus was found in an unaffected individual who was not considered to be at risk, potentially reducing the locus interval by 2 centimorgans. No mutations in the PABP2 gene were identified.


CONCLUSIONS
To our knowledge, our described family is only the second known kindred with a chromosome 14-linked MPD in whom the linkage has been unequivocally established. We did not detect signs of involvement of hand or finger extensors and neck muscles, seen in the original family with MPD1. The degree and frequency of proximal weakness seem to be more prominent than in other patients with MPD1. Haplotype analysis suggests that the gene is located between polymorphic microsatellite markers D14S283 and D14S1034 on chromosome 14q11-q13. The presence of cardiomyopathy in some affected individuals may help in the identification of candidate genes.
Hedera
Peter
P
Department of Neurology, University of Michigan Medical Center, Ann Arbor, USA. peter.hedera@vanderbilt.edu
Petty
Elizabeth M
EM
Bui
Melanie R
MR
Blaivas
Mila
M
Fink
John K
JK
D000328:Adult; D001706:Biopsy; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004576:Electromyography; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D039103:Poly(A)-Binding Protein II / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics
D039103:Poly(A)-Binding Protein II