Myoclonus-dystonia (M-D; OMIM 159900) is an autosomal dominant movement disorder characterized by alcohol responsive myoclonic jerks typically affecting the arms and axial muscles. Mutations in the epsilon-sarcoglycan (SGCE) gene on chromosome 7q21 were shown to cause M-D but not in all cases. Currently, in the literature mutations in SGCE are responsible for 20--50% of all cases of M-D. By direct sequencing, we have identified mutations in four families and we were able to find large deletions in two additional families using a semi-quantitative PCR-based DHPLC method. One of these families (family 2) has an 18 kb deletion that includes exons 2 and 3 while another family (family 6) has a 13 kb deletion covering exons 2 through 5. We have confirmed these large deletions by identifying the exact deletion breakpoints. In our cohort of 17 unrelated M-D families, 35% of patients with M-D have mutations in the SGCE gene. Previously, we characterized a large five-generation Canadian family with M-D (family 1) that did not have a mutation in SGCE and mapped a novel locus for this disorder to a 4 Mb region between the markers D18S1132 and D18S843 on 18p11 (OMIM number: 607488). Since additional informative STS markers were not found between the flanking recombinant and non-recombinant markers, we utilized single nucleotide polymorphisms (SNP) for fine-mapping. As a result, we identified three recombinant SNPs (rs385769, rs727951 and rs727952) in the proximal flanking region between markers D18S1163 and D18S843 in family 1. Our previous 4 Mb critical region has been reduced to 3.18 Mb, flanked by markers D18S1132 and rs385769. There are seven known genes and eight predicted genes within or very close to this region. We have sequenced all the exons and exon-intron boundaries of these seven known genes ( MGC17515, ZFP161, EPB41L3 (KIAA0987), L3MBT4, ARHGAP28 (FLJ10312), LAMA1, and PTPRM) and four predicted genes (LOC388459, LOC388460, LOC400643 and LOC388461) without identifying the causative mutations. Future studies should be directed to the investigation of the functional effects of the known SGCE mutations using in vitro and in vivo models. With respect to the identification of a novel gene in family 1, we will focus on the novel transcripts in the critical region based on gene prediction and EST (expressed sequence tag) mapping. Once the second M-D causing gene is identified, we will perform gene expression and cellular localization analyses of the mutated and wild type protein in tissues and generate a mouse model.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/29653 |
| Date | January 2007 |
| Creators | Han, Fabin |
| Publisher | University of Ottawa (Canada) |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 231 p. |
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