Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child
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《新英格兰医药杂志》
To the Editor: Schuelke et al. (June 24 issue)1 describe a child with muscle hypertrophy in association with a mutation in the myostatin gene. Another possible case of a myostatin mutation in an exceptionally strong child was described more than 2500 years ago in Greek mythology, in the story about Hercules. As an infant, Hercules strangled a snake in each hand when the goddess Hera tried to kill him. His legendary strength was obvious from the time of his birth, and it was not the result of any exercise program.
Branimir atipovi, M.D.
Department of Veteran Affairs
Mason City, IA 50401
bcatipovic@hotmail.com
References
Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004;350:2682-2688.
To the Editor: Schuelke et al. report a case of muscle hypertrophy associated with a mutation in the myostatin gene. The patient was homozygous for a guanine-to-adenine transition at nucleotide g.IVS1+5 — a mutation that may lead to missplicing. The mother was heterozygous for this mutation, and the father was unavailable. The authors hypothesize that the muscular hypertrophy was due to lack of myostatin. Although this hypothesis is attractive, another possibility was not addressed.
The myostatin gene (GDF8) maps to chromosome 2q32.1 in humans. Maternal isodisomy of chromosome 2 could explain the homozygosity of the described mutation. All or part of chromosome 2 may be subject to maternal imprinting.1,2 Abnormal imprinting can lead to growth abnormalities and tissue hypertrophy.3 For example, patients with the Beckwith–Wiedemann syndrome, a paternal imprinting disorder, may have macroglossia, hemihypertrophy (including muscle hemihypertrophy), and organomegaly; embryonal rhabdomyosarcoma has also been observed.4 Abnormal maternal imprinting usually, but not always, causes growth suppression.3 In the case reported by Schuelke et al., maternal isodisomy of chromosome 2 should be ruled out as a possible cause of the muscle hypertrophy.
Marc S. Williams, M.D.
Gundersen Lutheran Medical Center
La Crosse, WI 54601
mswillia@gundluth.org
References
University of Chicago. Human imprinting map. (Accessed August 13, 2004, at http://www.genes.uchicago.edu/upd/upd.html.)
Webb AL, Sturgiss S, Warwicker P, Robson SC, Goodship JA, Wolstenholme J. Maternal uniparental disomy for chromosome 2 in association with confined placental mosaicism for trisomy 2 and severe intrauterine growth retardation. Prenat Diagn 1996;16:958-962.
Butler MG. Imprinting disorders: non-Mendelian mechanisms affecting growth. J Pediatr Endocrinol Metab 2002;15:Suppl 5:1279-1288.
OMIM, Online Mendelian Inheritance in Man. Baltimore: Johns Hopkins University. (Accessed August 13, 2004, at http://www.ncbi.nlm.nih.gov/omim/.)
Dr. Schuelke and colleagues reply: Williams raises the question of whether the increased muscle mass in the child we describe might be due to an imprinting disorder and suggests that maternal isodisomy should be ruled out. Here we provide data to rule out uniparental isodisomy of chromosome 2 on the basis of microsatellite-marker analysis of specimens from the patient and his mother. We detected a founder haplotype for which the patient was homozygous in a 20-cM segment around the myostatin gene (Figure 1). Thus, the mode of inheritance in this child seems most likely to have been autosomal recessive, as it is in myostatin knockout mice1 and double-muscled cattle.2 There is additional evidence against an imprinting disorder: the effect of the myostatin splice-site mutation could be demonstrated in vitro after a genomic myostatin construct was transfected into mammalian cells. In this system, myostatin transcription is regulated by a cytomegalovirus promoter in which imprinting does not play a role.1 Most children with imprinting disorders have multiple-organ involvement and dysmorphic features,3,4 which was not the case with our patient.
Figure 1. Results of Haplotype Analysis.
Haplotype analysis of specimens from the patient and his mother was carried out with informative markers (deCODE) on chromosome 2 and reconstruction of the father's allele. The analysis revealed a founder haplotype (black bar) for which the patient was homozygous at the myostatin-gene locus. The numbers flanking the chromosomes depict the lengths (in base pairs) of the microsatellite markers from the maternal and the paternal alleles. Because the father's chromosome was reconstructed from the child's haplotypes, only one chromosome shows the numbers that refer to the length of the microsatellite markers. All codes beginning with D2 designate the names of the microsatellite markers from the deCODE marker set; D2 indicates that the markers are located on chromosome 2. The genetic distance between the markers is shown in centimorgans.
Birgit Uhlenberg, M.D.
Barbara Lucke
Markus Schuelke, M.D.
Charité University Medical Center
13353 Berlin, Germany
markus.schuelke@charite.de
References
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90.
Grobet L, Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 1997;17:71-74.
Buntinx IM, Hennekam RC, Brouwer OF, et al. Clinical profile of Angelman syndrome at different ages. Am J Med Genet 1995;56:176-183.
Engstrom W, Lindham S, Schofield P. Wiedemann-Beckwith syndrome. Eur J Pediatr 1988;147:450-457.
Branimir atipovi, M.D.
Department of Veteran Affairs
Mason City, IA 50401
bcatipovic@hotmail.com
References
Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004;350:2682-2688.
To the Editor: Schuelke et al. report a case of muscle hypertrophy associated with a mutation in the myostatin gene. The patient was homozygous for a guanine-to-adenine transition at nucleotide g.IVS1+5 — a mutation that may lead to missplicing. The mother was heterozygous for this mutation, and the father was unavailable. The authors hypothesize that the muscular hypertrophy was due to lack of myostatin. Although this hypothesis is attractive, another possibility was not addressed.
The myostatin gene (GDF8) maps to chromosome 2q32.1 in humans. Maternal isodisomy of chromosome 2 could explain the homozygosity of the described mutation. All or part of chromosome 2 may be subject to maternal imprinting.1,2 Abnormal imprinting can lead to growth abnormalities and tissue hypertrophy.3 For example, patients with the Beckwith–Wiedemann syndrome, a paternal imprinting disorder, may have macroglossia, hemihypertrophy (including muscle hemihypertrophy), and organomegaly; embryonal rhabdomyosarcoma has also been observed.4 Abnormal maternal imprinting usually, but not always, causes growth suppression.3 In the case reported by Schuelke et al., maternal isodisomy of chromosome 2 should be ruled out as a possible cause of the muscle hypertrophy.
Marc S. Williams, M.D.
Gundersen Lutheran Medical Center
La Crosse, WI 54601
mswillia@gundluth.org
References
University of Chicago. Human imprinting map. (Accessed August 13, 2004, at http://www.genes.uchicago.edu/upd/upd.html.)
Webb AL, Sturgiss S, Warwicker P, Robson SC, Goodship JA, Wolstenholme J. Maternal uniparental disomy for chromosome 2 in association with confined placental mosaicism for trisomy 2 and severe intrauterine growth retardation. Prenat Diagn 1996;16:958-962.
Butler MG. Imprinting disorders: non-Mendelian mechanisms affecting growth. J Pediatr Endocrinol Metab 2002;15:Suppl 5:1279-1288.
OMIM, Online Mendelian Inheritance in Man. Baltimore: Johns Hopkins University. (Accessed August 13, 2004, at http://www.ncbi.nlm.nih.gov/omim/.)
Dr. Schuelke and colleagues reply: Williams raises the question of whether the increased muscle mass in the child we describe might be due to an imprinting disorder and suggests that maternal isodisomy should be ruled out. Here we provide data to rule out uniparental isodisomy of chromosome 2 on the basis of microsatellite-marker analysis of specimens from the patient and his mother. We detected a founder haplotype for which the patient was homozygous in a 20-cM segment around the myostatin gene (Figure 1). Thus, the mode of inheritance in this child seems most likely to have been autosomal recessive, as it is in myostatin knockout mice1 and double-muscled cattle.2 There is additional evidence against an imprinting disorder: the effect of the myostatin splice-site mutation could be demonstrated in vitro after a genomic myostatin construct was transfected into mammalian cells. In this system, myostatin transcription is regulated by a cytomegalovirus promoter in which imprinting does not play a role.1 Most children with imprinting disorders have multiple-organ involvement and dysmorphic features,3,4 which was not the case with our patient.
Figure 1. Results of Haplotype Analysis.
Haplotype analysis of specimens from the patient and his mother was carried out with informative markers (deCODE) on chromosome 2 and reconstruction of the father's allele. The analysis revealed a founder haplotype (black bar) for which the patient was homozygous at the myostatin-gene locus. The numbers flanking the chromosomes depict the lengths (in base pairs) of the microsatellite markers from the maternal and the paternal alleles. Because the father's chromosome was reconstructed from the child's haplotypes, only one chromosome shows the numbers that refer to the length of the microsatellite markers. All codes beginning with D2 designate the names of the microsatellite markers from the deCODE marker set; D2 indicates that the markers are located on chromosome 2. The genetic distance between the markers is shown in centimorgans.
Birgit Uhlenberg, M.D.
Barbara Lucke
Markus Schuelke, M.D.
Charité University Medical Center
13353 Berlin, Germany
markus.schuelke@charite.de
References
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90.
Grobet L, Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 1997;17:71-74.
Buntinx IM, Hennekam RC, Brouwer OF, et al. Clinical profile of Angelman syndrome at different ages. Am J Med Genet 1995;56:176-183.
Engstrom W, Lindham S, Schofield P. Wiedemann-Beckwith syndrome. Eur J Pediatr 1988;147:450-457.