Obu

Chr.4

Chr. 10

EcoSI Blnl f.

-3kb EcoSI BM

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Fig. 4 Subtelomeric sequence exchange between 4q35 and 10q26 in 20% of the normal population. (From Ref. [11].) In the control population, 80% of individuals carry a standard configuration, with 4-type repeats on chromosome 4, and 10-type repeats on chromosome 10. In 10% of individuals, 4-derived repeats are also present on one of their chromosomes 10. Likewise, 10% of the control population carries 10-derived repeats on one of their chromosomes 4. (A) Five microliters of high-molecular-weight DNA digested sequentially with EcoRI and EcoRI/Blnl and hybridized with probe p13E11. In an informative situation, four different-sized EcoRI fragments are produced following a single digest: two derived from chromosome 4 and two from 10q. Digestion with enzyme BlnI will cleave two chromosome 10-specific fragments. Chromosome 4-specific fragments will be reduced by 3 kb, owing to the presence of a BlnI site proximal to the first repeat but distal to the EcoRI site (D). However, in 10% of individuals (B), 4-type repeats (BlnI-resistant) are translocated to chromosome 10; therefore with EcoRI/BlnI digestion, three alleles are seen instead of the expected two fragments. Similarly, 10% of control individuals (C) carry BlnI-sensitive repeats on one of their chromosomes 4; therefore with EcoRI/BlnI double digest, one allele (monosomy) is observed.

-3kb EcoSI BM

Blnl

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Blnl

Blnl

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Fig. 4 Subtelomeric sequence exchange between 4q35 and 10q26 in 20% of the normal population. (From Ref. [11].) In the control population, 80% of individuals carry a standard configuration, with 4-type repeats on chromosome 4, and 10-type repeats on chromosome 10. In 10% of individuals, 4-derived repeats are also present on one of their chromosomes 10. Likewise, 10% of the control population carries 10-derived repeats on one of their chromosomes 4. (A) Five microliters of high-molecular-weight DNA digested sequentially with EcoRI and EcoRI/Blnl and hybridized with probe p13E11. In an informative situation, four different-sized EcoRI fragments are produced following a single digest: two derived from chromosome 4 and two from 10q. Digestion with enzyme BlnI will cleave two chromosome 10-specific fragments. Chromosome 4-specific fragments will be reduced by 3 kb, owing to the presence of a BlnI site proximal to the first repeat but distal to the EcoRI site (D). However, in 10% of individuals (B), 4-type repeats (BlnI-resistant) are translocated to chromosome 10; therefore with EcoRI/BlnI digestion, three alleles are seen instead of the expected two fragments. Similarly, 10% of control individuals (C) carry BlnI-sensitive repeats on one of their chromosomes 4; therefore with EcoRI/BlnI double digest, one allele (monosomy) is observed.

EcoRl / EcoBl+ BM

of genes at 4q35.[19] YY1 is involved in repressing and activating a number of gene promoters. HMGB2 is a member of the family of high-mobility group (HMG) proteins. Nucleolin is involved in chromatin structure formation.

In FSHD patients who possess fewer D4Z4 repeats, the amount of suppressor is greatly reduced; therefore the disease may be seen as being caused by the derepression of the transcription of genes proximal to the repeats. The deletion of repeated 27-bp elements from the subtelomeric region of 4q may act in cis on neighboring tissue-specific genes by derepressing their transcriptional activity, thereby initiating a cascade of events that eventually leads to FSHD. This finding would account for the observation that monosomy of 4q35 does not result in FSHD expression.1-9-1 This elegant study is helping to unravel a new molecular mechanism for FSHD, which may well be found to underlie other genetic conditions.

However, in a recent study, the overexpression of genes in the FSHD candidate region was not reproduced.[20] It is possible that there is overexpression of a 4q35 gene in a small percentage of nuclei in the FSHD muscle fibers.

A polymorphism in the p-satellite repeats located distal to the D4Z4 repeat has recently been identified. This polymorphism, comprising alleles 4qA and 4qB, occurs with nearly equal frequencies in the normal population. FSHD is uniquely associated with 4qA al-lele.[22,23] Allele 4qA may have additional features that give rise to FSHD either by facilitating the derepression consequent to D4Z4 deletion, or, conceivably, by promoting D4Z4 deletion mutagenesis directly. It remains to be defined how allele 4qA relates to the complex that controls the expression of genes on 4q35. This finding may lead to a better understanding of the instability identified in the FSHD region.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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