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Linkage analyses of five chromosome 4 markers localizes the facioscapulohumeral muscular dystrophy (FSHD) gene to distal 4q35.

ABSTRACT: The genetic locus for facioscapulohumeral muscular dystrophy (FSHD) has been mapped to chromosome 4. We have examined linkage to five chromosome 4q DNA markers in 22 multigenerational FSHD families. Multipoint linkage analyses of the segregation of four markers in the FSHD families and in 40 multigenerational mapping families from the Centre d'Etude du Polymorphisme Humaine enabled these loci and FSHD to be placed in the following order: cen-D4S171-factor XI-D4S163-D4S139-FSHD-qter. One interval, D4S171-FSHD, showed significant sex-specific differences in recombination. Homogeneity tests supported linkage of FSHD to these 4q DNA markers in all of the families we studied. The position of FSHD is consistent with that generated by other groups as members of an international FSHD consortium.

SUBMITTER: Weiffenbach B

PROVIDER: S-EPMC1682668 | biostudies-other | 1992 Aug

REPOSITORIES: biostudies-other

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Linkage analyses of five chromosome 4 markers localizes the facioscapulohumeral muscular dystrophy (FSHD) gene to distal 4q35.

Weiffenbach B B Bagley R R Falls K K Hyser C C Storvick D D Jacobsen S J SJ Schultz P P Mendell J J Willems van Dijk K K Milner E C EC

American journal of human genetics 19920801 2

The genetic locus for facioscapulohumeral muscular dystrophy (FSHD) has been mapped to chromosome 4. We have examined linkage to five chromosome 4q DNA markers in 22 multigenerational FSHD families. Multipoint linkage analyses of the segregation of four markers in the FSHD families and in 40 multigenerational mapping families from the Centre d'Etude du Polymorphisme Humaine enabled these loci and FSHD to be placed in the following order: cen-D4S171-factor XI-D4S163-D4S139-FSHD-qter. One interval ...[more]

PMID: 1642240

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The mapping of chromosome 4q markers in relation to facioscapulohumeral muscular dystrophy (FSHD).

Project description:Four DNA markers on the distal long arm of chromosome 4 have been analyzed for their linkage relationship to facioscapulohumeral muscular dystrophy (FSHD) in a series of 23 families with this disease. Two hypervariable markers, pH30 (D4S139) and EFD 139.1 (D4S184), both show close linkage with the disorder, with a maximum recombination fraction (theta max) of .02 and a maximum lod score (Zmax) of 36.77 and 34.50, respectively; two other markers, the locus for factor XI (F11) and the microsatellite marker Mfd22 (D4S171), both show less close linkage, with respective theta max of .16 (Zmax = 3.40) for F11 and .24 (Zmax = 1.61) for D4S171. While the relative ordering and orientation of the loci on the chromosome remain provisional, analysis of 15 individual recombination events in seven families supports the order D4S171-F11-D4S184-D4S139-FSHD, with the disease locus telomeric to all four markers.

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Reachable workspace in facioscapulohumeral muscular dystrophy (FSHD) by Kinect.

Project description:A depth-ranging sensor (Kinect) based upper extremity motion analysis system was applied to determine the spectrum of reachable workspace encountered in facioscapulohumeral muscular dystrophy (FSHD).Reachable workspaces were obtained from 22 individuals with FSHD and 24 age- and height-matched healthy controls. To allow comparison, total and quadrant reachable workspace relative surface areas (RSAs) were obtained by normalizing the acquired reachable workspace by each individual's arm length.Significantly contracted reachable workspace and reduced RSAs were noted for the FSHD cohort compared with controls (0.473?±?0.188 vs. 0.747?±?0.082; P?<?0.0001). With worsening upper extremity function as categorized by the FSHD evaluation subscale II?+?III, the upper quadrant RSAs decreased progressively, while the lower quadrant RSAs were relatively preserved. There were no side-to-side differences in reachable workspace based on hand-dominance.This study demonstrates the feasibility and potential of using an innovative Kinect-based reachable workspace outcome measure in FSHD.

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Transcription profiling of human Facioscapulohumeral muscular dystrophy (FSHD) muscle profiles

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Experiment Overall Design: Comparison of the profiles of FSHD to 13 other conditions for disease-specific changes. The 13 conditions are NHM (Normal healthy muscle) n=15; JDM (Juvenile dermatomyositis) n=25; HSP (Human spastic paraplegia) n=4; FSHD (facioscapulohumeral dystrophy) unaffected n=5, affected n=9; FKRP (Fukutin related protein deficiency) n=7; ED-L (Emery-Dreifuss muscular dystrophy, lamin A/C deficiency) n=4; ED-E (Emery-Dreifuss muscular dystrophy, emerin deficiency) n=4; DYSF (dysferlinopathy) n=10; DMD (Duchenne Muscular Dystrophy) n=10; CALP (Calpain-3 deficiency) n=10; BMD (Becker Muscular Dystrophy) n=5; AQM (Acute quadriplegic myopathy) n=5; ALS (Amyotrophic lateral sclerosis) n=9.

2008-06-16 | E-GEOD-9397 | biostudies-arrayexpress

Genetic linkage map of facioscapulohumeral muscular dystrophy and five polymorphic loci on chromosome 4q35-qter.

Project description:A genetic map of five polymorphic markers in the area of the facioscapulohumeral muscular dystrophy (FSHD) gene on chromosome 4q35-qter has been constructed. With these five markers, a number of recombinants have been identified that allow ordering of the marker and the disease loci. The most likely locus order and the relative position of the FSHD gene supported by the recombinants is centromere-D4S171-F11-D4S187-D4S163-D4S139-FS HD-telomere. However, at least one recombination event appears to be inconsistent with this order and suggests a location of FSHD proximal to D4S139.

| S-EPMC1682695 | biostudies-literature

Facioscapulohumeral muscular dystrophy.

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a common type of adult muscular dystrophy and is divided into types 1 and 2 based on genetic mutation. Clinically, both FSHD types often show asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms followed by the distal then proximal lower extremities. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both types share a common downstream mechanism, making it possible for future disease-directed therapies to be effective for both FSHD types.

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Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a dynamic nuclear and sarcomeric protein.

Project description:Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for mediating FSHD pathophysiology, however, very little is known about the endogenous FRG1 protein. This study uses immunocytochemistry (ICC) and histology to provide insight into FRG1's role in vertebrate muscle development and address its potential involvement in FSHD pathophysiology. In cell culture, primary myoblast/myotube cultures, and mouse and human muscle sections, FRG1 showed distinct nuclear and cytoplasmic localizations and nuclear shuttling assays indicated the subcellular pools of FRG1 are linked. During myoblast differentiation, FRG1's subcellular distribution changed dramatically with FRG1 eventually associating with the matured Z-discs. This Z-disc localization was confirmed using isolated mouse myofibers and found to be maintained in adult human skeletal muscle biopsies. Thus, FRG1 is not likely involved in the initial assembly and alignment of the Z-disc but may be involved in sarcomere maintenance or signaling. Further analysis of human tissue showed FRG1 is strongly expressed in arteries, veins, and capillaries, the other prominently affected tissue in FSHD. Overall, we show that in mammalian cells, FRG1 is a dynamic nuclear and cytoplasmic protein, however in muscle, FRG1 is also a developmentally regulated sarcomeric protein suggesting FRG1 may perform a muscle-specific function. Thus, FRG1 is the only FSHD candidate protein linked to the muscle contractile machinery and may address why the musculature and vasculature are specifically susceptible in FSHD.

| S-EPMC3030934 | biostudies-literature

Single-molecule optical mapping enables quantitative measurement of D4Z4 repeats in facioscapulohumeral muscular dystrophy (FSHD).

Project description:PurposeFacioscapulohumeral muscular dystrophy (FSHD) is a common adult muscular dystrophy. Over 95% of FSHD cases are associated with contraction of the D4Z4 tandem repeat (~3.3 kb per unit) at 4q35 with a specific genomic configuration (haplotype) called 4qA. Molecular diagnosis of FSHD typically requires pulsed-field gel electrophoresis with Southern blotting. We aim to develop novel genomic and computational methods for characterising D4Z4 repeat numbers in FSHD.MethodsWe leveraged a single-molecule optical mapping platform that maps locations of restriction enzyme sites on high molecular weight (>150 kb) DNA molecules. We developed bioinformatics methods to address several challenges, including the differentiation of 4qA with 4qB alleles, the differentiation of 4q35 and 10q26 segmental duplications, the quantification of repeat numbers with different enzymes that may or may not have recognition sites within D4Z4 repeats. We evaluated the method on 25 human subjects (13 patients, 3 individual control subjects, 9 control subjects from 3 families) labelled by the Nb.BssSI and/or Nt.BspQI enzymes.ResultsWe demonstrated that the method gave a direct quantitative measurement of repeat numbers on D4Z4 repeats with 4qA allelic configuration and the levels of postzygotic mosaicism. Our method had high concordance with Southern blots from several cohorts on two platforms (Bionano Saphyr and Bionano Irys), but with improved quantification of repeat numbers.ConclusionWhile the study is limited by small sample size, our results demonstrated that single-molecule optical mapping is a viable approach for more refined analysis on genotype-phenotype relationships in FSHD, especially when postzygotic mosaicism is present.

| S-EPMC7029236 | biostudies-literature

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