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The hypothesis that a selective deletion of the muscle promoter causes cardiomyopathy without skeletal myopathy is not supported by other published reports of subjects with this mutation3. The report by Towbin et al. demonstrates that the muscle promoter is intact in the families they studied. Thus, this mutation is not unique for the expression of cardiac symptoms. Furthermore, the hypothesis put forth by Muntoni et al. that "the brain promoter is driving relatively high levels of transcription in skeletal muscle but not in the heart" is not supported by our report,4 which was cited in their article. We demonstrated that the brain promoter is capable of driving dystrophin transcription in the human heart, perhaps more so than in skeletal muscle, a finding that contradicts their statement. The lack of molecular data from cardiac tissue (i.e., endomyocardial-biopsy specimens from an affected family member) makes it very difficult to speculate how the muscle-promoter deletion in the family Muntoni et al. studied might selectively affect dystrophin function in the heart, or even whether it has such an effect. Further investigation is required to uncover the molecular mechanisms that distinguish cardiac-muscle from skeletal-muscle dysfunction in these families.
Roger D. Bies, M.D.
University of Colorado Health Sciences Center
Denver, CO 80262
References
Another term used in a questionable manner is "obligate carriers," which is used for all four carrier females in the pedigree. This term can correctly be used to apply only to subjects whose carrier status is obvious on the basis of pedigree data; in this family, only Subject I-1 should be called an obligate carrier. The other three (Subjects I-5, II-3, and II-4) are not obligate carriers, since their carrier status was based on the molecular studies performed and not on pedigree information.
Since reports of genetic studies are increasingly read by nongeneticists, it is important to use correct terminology in order to avoid confusion.
Martin Roubicek, M.D.
Universidad Nacional de Mar del Plata
7600 Mar del Plata, Argentina
References
We have now studied three families with X-linked dilated cardiomyopathy, and in all subjects the muscle-promoter and exon 1 regions are intact. Using the same primers as Muntoni et al., including DYSMSB (which was deleted in the family described), we could not find any deletions in the probands of our families (Figure 1). Furthermore, extensive sequencing of this region revealed no abnormalities. Also unsupported is their hypothesis that selective deletion of the muscle promoter leads to cardiomyopathy without skeletal disease and that the brain promoter is selectively "driving . . . high levels of transcription in skeletal muscle but not in the heart." A similar deletion, but without selective cardiac disease (in fact, with no cardiac disease), has been described2,3. In addition, Bies et al.4 demonstrated that the brain promoter is capable of driving dystrophin transcription in the human heart at a level even greater than that seen in skeletal muscle, directly contradicting, rather than supporting, the results of Muntoni et al.
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Jeffrey A. Towbin, M.D.
Rocio Ortiz-Lopez, M.S.
Baylor College of Medicine
Houston, TX 77030
References
To the Editor: I am grateful to Dr. Roubicek for his comment on the use of the term "obligate carrier." With respect to his comment on Table 1, an error was introduced during the preparation and editing of column 11. A revised version is shown.
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We initially hypothesized that the brain promoter was driving dystrophin transcription in the skeletal muscle of our patients. We have now found, after detailed quantitation of the reverse-transcribed messenger RNA, that this is the case (unpublished data). Because of the unavailability of cardiac tissue, we have not studied transcription in the heart of the proband.
The work of Bies et al. showed that the brain promoter is not capable of driving dystrophin transcription in human Purkinje fibers or in the heart of the mouse3. The importance of the faint signal obtained from the heart in humans is difficult to interpret because no quantitation of transcription was attempted4 and the contributing role of contaminating smooth muscle was not established.
Regardless of the mechanism responsible for the dissociation between the skeletal-muscle and cardiac-muscle involvement in our patients, their phenotype is undoubtedly due to a dystrophin mutation, and this is what we emphasized. We proposed that biochemical and genetic screening for a dystrophinopathy should be performed in all families with X-linked dilated cardiomyopathy. The observations of Dr. Towbin and Mr. Ortiz-Lopez and those of Dr. Bies confirm that this recommendation is valid.
It is likely that more than one mutation will be found in this group of patients, as is the case for both Duchenne's and Becker's muscular dystrophies. However, most reports of the families with this disease (including one Italian family [Angelini C: personal communication] and seven Japanese families [Takeda S: personal communication]) in which a proper biochemical evaluation was performed revealed skeletal-muscle dystrophin of normal molecular weight although in lower than normal levels, strongly reinforcing the view that mutations in regulatory regions of the gene are likely to be implicated in this phenotype.
Francesco Muntoni, M.D.
Royal Postgraduate Medical School
London, W12 ONN, United Kingdom
References
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