Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization

Wijmenga, Cisca; Padberg, George W.; Moerer, Petra; Wiegant, J.; Liem, Linda; Brouwer, Oebele F.; Milner, Eric C. B.; Weber, James L.; Ommen, Gert‐Jan B. van; Sandkuyl, L. A.; Frants, Rune R.

doi:10.1016/0888-7543(91)90348-i

Cited by 108 publications

(40 citation statements)

References 9 publications

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“…The tip of chromosome 4q35 has been identified as the locus for FSHD1 (Wijmenga et al, 1991). The identification of the TUBB4Q gene in the region represents a strong FSHD1 candidate gene, as the protein might affect the functionality of the microtubule complex.…”

Section: Discussionmentioning

confidence: 99%

“…One of the members, designated TUBB4Q, resides close to the telomere of chromosome 4q35. This chromosome region has been linked to facioscapulohumeral muscular dystrophy (FSHD1) (Wijmenga et al, 1991), a progressive autosomal dominant myopathy, preferentially affecting facial, shoulder girdle and upper-arm muscles (Padberg, Fig. 1.…”

confidence: 99%

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Identification of a novel β-tubulin subfamily with one member (TUBB4Q) located near the telomere of chromosome region 4q35

Geel

Deutekom

Staalduinen

et al. 2000

Cytogenet Genome Res

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The human β-tubulin supergene family consists of several isotypes with many associated pseudogenes. Here we report the identification of yet another β-tubulin sequence designated TUBB4Q. This tubulin maps 80 kb proximal to the facioscapulohumeral muscular dystrophy (FSHD1) associated D4Z4 repeats on chromosome 4q35. The genomic structure contains four exons encoding a putative protein of 434 amino acids. The TUBB4Q nucleotide and protein sequence show 87% and 86% homology to β2-tubulin, respectively. Although the genomic structure shows all functional aspects of a genuine gene, no transcript could be detected. TUBB4Q-related sequences were identified on multiple chromosomes. Since these sequences mutually exhibit a high nucleotide sequence homology, they presumably belong to a novel subfamily of β-tubulin genes. Although the chromosome 4q35 tubulin-member probably represents a pseudogene, ectopic expression due to a postulated position effect variegation (PEV), makes TUBB4Q an ideal dominant-negative candidate gene for FSHD1.

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Section: Discussionmentioning

confidence: 99%

Identification of a novel β-tubulin subfamily with one member (TUBB4Q) located near the telomere of chromosome region 4q35

Geel

Deutekom

Staalduinen

et al. 2000

Cytogenet Genome Res

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show abstract

“…FSHD is characterized by weakness and atrophy of muscles of the face, upper arms, and shoulder girdle. Linkage analysis has mapped the FSHD locus to the subtelomeric region of the long arm of chromosome 4 (2).…”

mentioning

confidence: 99%

Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts

Petrov

Pirozhkova

Carnac

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Fascioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder linked to partial deletion of integral numbers of a 3.3 kb polymorphic repeat, D4Z4, within the subtelomeric region of chromosome 4q. Although the relationship between deletions of D4Z4 and FSHD is well established, how this triggers the disease remains unclear. We have mapped the DNA loop domain containing the D4Z4 repeat cluster in human primary myoblasts and in murine-human hybrids. A nuclear matrix attachment site was found located in the vicinity of the repeat. Prominent in normal human myoblasts and nonmuscular human cells, this site is much weaker in muscle cells derived from FSHD patients, suggesting that the D4Z4 repeat array and upstream genes reside in two loops in nonmuscular cells and normal human myoblasts but in only one loop in FSHD myoblasts. We propose a model whereby the nuclear scaffold͞matrix attached region regulates chromatin accessibility and expression of genes implicated in the genesis of FSHD. The disorder is related to a short repeat array that remains after deletion of an integral number of tandemly arrayed 3.3-kb repeat units on chromosome 4. The size of this polymorphic locus (D4Z4) varies in normal individuals from 35 to 300 kb, whereas in FSHD patients it is consistently shorter than 35 kb (3). Partial deletion of the D4Z4 array on chromosome 4 ultimately leads to FSHD and is currently used as a diagnostic tool in genetic counseling to predict the probability of the disease (1,(3)(4)(5). A correlation exists between the extent of the deletion and its clinical expression: Indeed, patients with one to three repeats develop an early FSHD, whereas individuals with nine to 10 repeats exhibit a weaker form of the disease (5).Extensive efforts to identify gene transcripts associated with the 4q35-specific D4Z4 repeat, as potential FSHD candidate genes, have been largely unsuccessful (6). The 3.3-kb D4Z4 elements contain a cryptic DUX4 gene potentially coding for a double homeodomain protein (7), and an overall perturbation of mRNA expression profiles can be observed in FSHD patients (8-10), but the disease appears to result from an as yet unexplained mechanism with a genetic alteration not residing within a causative gene for the disease.The 4q35 genomic region ( Fig. 1) displays heterochromatic features and might exert repressive effects on neighboring genes with a mechanism similar to position effect variegation. A decreased D4Z4 repeat number consistently results in inappropriate up-regulation of adjacent FRG2, FRG1, and Ant1 in FSHD muscle (11-13). It has also been shown that a transcriptional repressor complex binds D4Z4, whose deletion would trigger overexpression by lack of repression (11). Indeed, overexpression of FRG1 in transgenic mice provokes a phenotype similar to that of FSHD (14). However, such a model of position effect has been recently challenged in two reports of an apparent lack of up-regulation of any 4q35 gene and because of the histone H4 acetylation state in FSHD lymph...

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“…2) (Wijmenga et al, 1990;1991). Subsequently, it has been shown that FSHD is associated with deletions within the complex tandem repeal locus D4Z4 (Wijmenga et al, 1992).…”

Section: Facioscapulohumeral Muscular Dystrophy (Fshd)mentioning

confidence: 99%

Report of the Fourth International Workshop on Human Chromosome 4 Mapping 1996

Rieß

Ommen²

1996

Cytogenet Genome Res

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Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization

Cited by 108 publications

References 9 publications

Identification of a novel β-tubulin subfamily with one member (TUBB4Q) located near the telomere of chromosome region 4q35

Identification of a novel β-tubulin subfamily with one member (TUBB4Q) located near the telomere of chromosome region 4q35

Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts

Report of the Fourth International Workshop on Human Chromosome 4 Mapping 1996

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