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Updated: Aug 25, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3)
Henna Haravuori1, H Annika Siitonen, Ibrahim Mahjneh
1Department of Molecular Medicine, National Public Health Institute, P.O. Box 104, FIN-00251 Helsinki, Finland. henna.haravuori@helsinki.fi
Abstract:
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.
Insights
Researchers identified two chromosomal regions linked to adult-onset distal myopathy (MPD3). Further studies are needed to pinpoint the specific gene responsible for this progressive muscle disorder.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Adult onset distal myopathy (MPD3) is a recently described autosomal dominant condition.
- Symptoms typically begin around age 30 with hand clumsiness and stumbling, progressing to involve intrinsic hand muscles, lower legs, forearms, and proximal muscles.
- Muscle biopsies reveal dystrophic changes and rimmed vacuoles.
Purpose of the Study:
- To identify the genetic locus associated with MPD3 through a genome-wide scan.
- To investigate potential candidate genes within the linked chromosomal regions.
Main Methods:
- Genome-wide scan performed on affected families.
- Multipoint linkage analyses to determine chromosomal regions with significant linkage.
- Haplotype analysis to track disease segregation.
- Sequence analysis of candidate genes (myosin light chain 1 slow-twitch muscle A and ankyrin 1).
Main Results:
- Significant evidence for linkage to two distinct chromosomal regions: 8p22-q11 and 12q13-q22.
- Maximum multipoint LOD score of 3.01 for both regions, indicating equal likelihood without further data.
- Haplotype analysis confirmed a specific haplotype segregating with the disease in both loci.
- No mutations were found in the coding sequences of the analyzed candidate genes.
Conclusions:
- The genetic basis of MPD3 is linked to two chromosomal regions, 8p22-q11 and 12q13-q22.
- Additional family material is required to differentiate between the two identified loci.
- Candidate gene sequencing did not reveal causative mutations, suggesting the mutation may lie in non-coding regions or other unanalyzed genes.
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