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X CHROMOSOME IN DUCHENNE MUSCULAR DYSTROPHY
1251 X CHROMOSOME IN DUCHENNE MUSCULAR
DYSTROPHY
SiR,—Various methods of carrier detection of Duchenne muscular dystrophy (DMD) are in use, and antenatal sex determination has provided the opportunity to selectively abort any male fetus. This could lead to the unnecessary termination of at least 50% of such pregnancies, which would not be affected with DMD. Therefore a reliable means of testing for an affected male fetus is
required. Females with DMD are rare. In all six published reports of affected females who carry an X-autosome translocationl-6 the in the X chromosome has been at Xp21, although the involved differs from patient to patient. Since the condition is X-linked it is reasonable to suggest that the gene for DMD is situated at, or very near, this common breakpoint Xp21. Katsantoni7 examined the metaphase chromosomes of obligate carriers and was unable to detect any lesion in the X chromosome and postulated that any deficiency involved must be less than half of the width of a band. Since then increased use has been made of highresolution banding in cytogenetics, which involves examining chromosomes at prometaphase or even prophase. Using standard high-resolution banding techniques we have examined the chromosomes of nine boys with DMD. Similar preparations from normal males and females were examined concurrently. We have been unable to detect any alteration in the banding pattern of the X chromosome. In each case bands Xp21 -1, 21- 2, and 21 3 could be resolved and there appeared to be no difference between the X chromosomes of patients and controls. Examples from patients and controls are shown in the figure. Despite the rarity of affected females it is surprising that none has been reported showing a deletion at Xp21. Neither has an affected male been found with an X-autosome translocation. Either of these
breakpoint autosome
F. Duchenne dystrophy in a female with a structurally abnormal X chromosome. Neurology 1974, 24: 356. 2. Verellen C, Freund M, De Meyer R, Laterre C, Scholberg B, Frederic J. Progressive muscular dystrophy of the Duchenne type in a young girl associated with an aberration of chromosome X Excerpta Med Int Congr Ser 1977: 92. 3. Canki N, Dutrillaux B, Tivadar I. Dystrophie musculaire de Duchenne chez une petite fille porteuse d’une translocation t(X,3) (p21;q13) de novo. Ann Genet (Paris 1979; 1.
Berg G, Conte
22: 35-39 4. Lindenbaum RH, Clarke G, Patel
C, Moncrieff M, Hughes JT. Muscular dystrophy in X; 1 translocation female suggests that Duchenne locus is on X chromosome short arm. J Ned Genet 1979; 16: 389-92. 5. Greenstein RM, Reardon MP, Chan TS, Middleton AB, Mulivor RA, Greene AE, Coriell LL. An (X;11) translocation in a girl with Duchenne muscular dystrophy Repository identification no. GM1695. Cytogenet Cell Genet 1980; 27: 268. 6. Jacobs PA, Hunt PA, Mayer M, Bart RD Duchenne muscular dystrophy (DMD) in a an
female with an X/autosome translocation. further evidence that the DMD locus is at
Xp21. Am J Hum Genet 1981, 33: 7. Katsantoni A. The X chromosome 1976; 9: 371-73.
-
X-chromosomes
(right). (Birth
513-18.
in
Duchenne’s muscular
dystrophy
Clin Genet
situations would be more readily detected than a small deletion in the single X chromosome of an affected male. The finding of an X-autosome translocation with a break-point at Xp21 in six females with DMD may have been fortuitous. Studies of families in which there was information on the segregation of DMD and Xg have found that there was no measurable linkage between these two genes.8 Xg has been assigned to band Xp229 albeit probably in the distal portion. If the functional gene for DMD is in band Xp2l, it could be expected to show some linkage with the Xg locus in the adjacent band, unless there is a high crossover frequency in the terminal band of the Xp arm. However, it is still questionable whether Xp21 is the site of the gene and it seems clear that the resolution afforded by chromosome banding alone is insufficient to detect either carrier or sufferer. The development of a DNA specific probe should give better grounds for optimism in the search for a of detecting both carriers and patients with this
reliable disease.9 means
G. SPOWART K. E. BUCKTON
M.R C. Clinical and Population Cytogenetics Unit and Department of Human Genetics, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU
R. SKINNER A. E. H. EMERY
CORTICOTROPIN RELEASING FACTOR STIMULATES ACTH RELEASE FROM HUMAN PITUITARY CORTICOTROPIC TUMOUR CELLS IN CULTURE
SiR,-The 41 aminoacid residue peptide from ovine hypothalami with potent corticotropin (ACTH) releasing activity in both rat (in vitro and in vivo)u2 and man (in vivo)3 is a potentially useful aid for the investigation ofhypothalamic-pituitary disease. We have looked for direct stimulatory effects of ovine corticotropin releasing factor (CRF) on ACTH secretion from human pituitary tumour cells in culture. ACTH secreting pituitary tumours were obtained from one patient with active Cushing’s disease and two with Nelson’s Blyth H, Carter CO, Dubowitz V, Emery AEH, Gavin J, Johnston HA, McKusick VA, Race RR, Sanger R, Tippett P. Duchenne’s muscular dystrophy and the Xg blood groups: a search for linkage. J Med Genet 1965; 2: 157-160. 9. Human Gene Mapping 6 (Oslo Conference 1981). (In press) 10. Emery AEH. Recombinant DNA technology. Lancet 1981, ii: 1406-09. 1. Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of a corticotropin and &bgr;-endorphin. 8.
Science 1981; 213: 1394-97. C, Brownstein M, Spiess J, Rivier J, Vale W. In vivo corticotropin-releasing activity-induced secretion of adrenocorticotropin, &bgr;-endorphin, and corticosterone. Endocrinology 1982; 110: 272-78. 3. Grossman A, Nieuwenhuyzen Kruseman AC, Perry L, et al. New hypothalamic hormone, corticotropin-releasing factor, specifically stimulates the release of adreno-corticotropic hormone and cortisol in man. Lancet 1982; i: 921-22.
2. Rivier
-
selected from DMD patients (top) and controls (bottom) with Defects Orig Art Ser 1981: 17: no. ).
I
, the ISCN (1981) templates for
400 bands
(left) and 850
bands -
DYSTROPHY
SiR,—Various methods of carrier detection of Duchenne muscular dystrophy (DMD) are in use, and antenatal sex determination has provided the opportunity to selectively abort any male fetus. This could lead to the unnecessary termination of at least 50% of such pregnancies, which would not be affected with DMD. Therefore a reliable means of testing for an affected male fetus is
required. Females with DMD are rare. In all six published reports of affected females who carry an X-autosome translocationl-6 the in the X chromosome has been at Xp21, although the involved differs from patient to patient. Since the condition is X-linked it is reasonable to suggest that the gene for DMD is situated at, or very near, this common breakpoint Xp21. Katsantoni7 examined the metaphase chromosomes of obligate carriers and was unable to detect any lesion in the X chromosome and postulated that any deficiency involved must be less than half of the width of a band. Since then increased use has been made of highresolution banding in cytogenetics, which involves examining chromosomes at prometaphase or even prophase. Using standard high-resolution banding techniques we have examined the chromosomes of nine boys with DMD. Similar preparations from normal males and females were examined concurrently. We have been unable to detect any alteration in the banding pattern of the X chromosome. In each case bands Xp21 -1, 21- 2, and 21 3 could be resolved and there appeared to be no difference between the X chromosomes of patients and controls. Examples from patients and controls are shown in the figure. Despite the rarity of affected females it is surprising that none has been reported showing a deletion at Xp21. Neither has an affected male been found with an X-autosome translocation. Either of these
breakpoint autosome
F. Duchenne dystrophy in a female with a structurally abnormal X chromosome. Neurology 1974, 24: 356. 2. Verellen C, Freund M, De Meyer R, Laterre C, Scholberg B, Frederic J. Progressive muscular dystrophy of the Duchenne type in a young girl associated with an aberration of chromosome X Excerpta Med Int Congr Ser 1977: 92. 3. Canki N, Dutrillaux B, Tivadar I. Dystrophie musculaire de Duchenne chez une petite fille porteuse d’une translocation t(X,3) (p21;q13) de novo. Ann Genet (Paris 1979; 1.
Berg G, Conte
22: 35-39 4. Lindenbaum RH, Clarke G, Patel
C, Moncrieff M, Hughes JT. Muscular dystrophy in X; 1 translocation female suggests that Duchenne locus is on X chromosome short arm. J Ned Genet 1979; 16: 389-92. 5. Greenstein RM, Reardon MP, Chan TS, Middleton AB, Mulivor RA, Greene AE, Coriell LL. An (X;11) translocation in a girl with Duchenne muscular dystrophy Repository identification no. GM1695. Cytogenet Cell Genet 1980; 27: 268. 6. Jacobs PA, Hunt PA, Mayer M, Bart RD Duchenne muscular dystrophy (DMD) in a an
female with an X/autosome translocation. further evidence that the DMD locus is at
Xp21. Am J Hum Genet 1981, 33: 7. Katsantoni A. The X chromosome 1976; 9: 371-73.
-
X-chromosomes
(right). (Birth
513-18.
in
Duchenne’s muscular
dystrophy
Clin Genet
situations would be more readily detected than a small deletion in the single X chromosome of an affected male. The finding of an X-autosome translocation with a break-point at Xp21 in six females with DMD may have been fortuitous. Studies of families in which there was information on the segregation of DMD and Xg have found that there was no measurable linkage between these two genes.8 Xg has been assigned to band Xp229 albeit probably in the distal portion. If the functional gene for DMD is in band Xp2l, it could be expected to show some linkage with the Xg locus in the adjacent band, unless there is a high crossover frequency in the terminal band of the Xp arm. However, it is still questionable whether Xp21 is the site of the gene and it seems clear that the resolution afforded by chromosome banding alone is insufficient to detect either carrier or sufferer. The development of a DNA specific probe should give better grounds for optimism in the search for a of detecting both carriers and patients with this
reliable disease.9 means
G. SPOWART K. E. BUCKTON
M.R C. Clinical and Population Cytogenetics Unit and Department of Human Genetics, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU
R. SKINNER A. E. H. EMERY
CORTICOTROPIN RELEASING FACTOR STIMULATES ACTH RELEASE FROM HUMAN PITUITARY CORTICOTROPIC TUMOUR CELLS IN CULTURE
SiR,-The 41 aminoacid residue peptide from ovine hypothalami with potent corticotropin (ACTH) releasing activity in both rat (in vitro and in vivo)u2 and man (in vivo)3 is a potentially useful aid for the investigation ofhypothalamic-pituitary disease. We have looked for direct stimulatory effects of ovine corticotropin releasing factor (CRF) on ACTH secretion from human pituitary tumour cells in culture. ACTH secreting pituitary tumours were obtained from one patient with active Cushing’s disease and two with Nelson’s Blyth H, Carter CO, Dubowitz V, Emery AEH, Gavin J, Johnston HA, McKusick VA, Race RR, Sanger R, Tippett P. Duchenne’s muscular dystrophy and the Xg blood groups: a search for linkage. J Med Genet 1965; 2: 157-160. 9. Human Gene Mapping 6 (Oslo Conference 1981). (In press) 10. Emery AEH. Recombinant DNA technology. Lancet 1981, ii: 1406-09. 1. Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of a corticotropin and &bgr;-endorphin. 8.
Science 1981; 213: 1394-97. C, Brownstein M, Spiess J, Rivier J, Vale W. In vivo corticotropin-releasing activity-induced secretion of adrenocorticotropin, &bgr;-endorphin, and corticosterone. Endocrinology 1982; 110: 272-78. 3. Grossman A, Nieuwenhuyzen Kruseman AC, Perry L, et al. New hypothalamic hormone, corticotropin-releasing factor, specifically stimulates the release of adreno-corticotropic hormone and cortisol in man. Lancet 1982; i: 921-22.
2. Rivier
-
selected from DMD patients (top) and controls (bottom) with Defects Orig Art Ser 1981: 17: no. ).
I
, the ISCN (1981) templates for
400 bands
(left) and 850
bands -