Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3).
We recently described a new type of adult onset distal myopathy (MPD3) with autosomal dominant inheritance. The onset of symptoms is around the age of 30 and the characteristic first symptoms include clumsiness of the hands and stumbling. The thenar and hypothenar muscles are involved at the onset. The disease progressed to the intrinsic muscles of the hands, both anterior and posterior muscle compartments of the lower legs, the forearm muscles, and later to the proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the muscle biopsy. We have performed a genome wide scan here in order to identify the MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11 and 12q13-q22, provided significant evidence for linkage in this family. Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01 for both chromosomal regions and haplotype analysis showed a specific haplotype segregating with the disease for both loci. It is thus impossible to distinguish between two loci without additional family material. Two obvious regional candidate genes, encoding muscular proteins became subjects for sequence analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the coding sequence.
Haravuori
Henna
H
Department of Molecular Medicine, National Public Health Institute, P.O. Box 104, FIN-00251 Helsinki, Finland. henna.haravuori@helsinki.fi
Siitonen
H Annika
HA
Mahjneh
Ibrahim
I
Hackman
Peter
P
Lahti
Laura
L
Somer
Hannu
H
Peltonen
Leena
L
Kestilä
Marjo
M
Udd
Bjarne
B
D000328:Adult; D017487:Ankyrins / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods; D002881:Chromosomes, Human, Pair 12; D002898:Chromosomes, Human, Pair 8; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D018740:Genetic Heterogeneity; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics*; D018994:Myosin Light Chains / Q000235:genetics; D010375:Pedigree; D010641:Phenotype
D017487:Ankyrins; D005819:Genetic Markers; D018994:Myosin Light Chains