Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene

C. A. Thornton, J. P. Wymer, Zachary Simmons, C. McClain, R. T. Moxley

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy,- insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation in cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.

Original languageEnglish (US)
Pages (from-to)407-409
Number of pages3
JournalNature Genetics
Volume16
Issue number4
DOIs
StatePublished - Aug 14 1997

Fingerprint

Myotonic Dystrophy
Genes
Muscles
Trinucleotide Repeat Expansion
Trinucleotide Repeats
Heart Block
Myoblasts
3' Untranslated Regions
Transgenes
Knockout Mice
Cataract
Protein Kinases
Chromatin
Atrophy
Insulin Resistance
Myocardium
Chromosomes
Gene Expression
Mutation

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Thornton, C. A. ; Wymer, J. P. ; Simmons, Zachary ; McClain, C. ; Moxley, R. T. / Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. In: Nature Genetics. 1997 ; Vol. 16, No. 4. pp. 407-409.
@article{e814412e90f74b5793e4f1501dd2dcd0,
title = "Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene",
abstract = "Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy,- insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation in cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.",
author = "Thornton, {C. A.} and Wymer, {J. P.} and Zachary Simmons and C. McClain and Moxley, {R. T.}",
year = "1997",
month = "8",
day = "14",
doi = "10.1038/ng0897-407",
language = "English (US)",
volume = "16",
pages = "407--409",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",

}

Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. / Thornton, C. A.; Wymer, J. P.; Simmons, Zachary; McClain, C.; Moxley, R. T.

In: Nature Genetics, Vol. 16, No. 4, 14.08.1997, p. 407-409.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene

AU - Thornton, C. A.

AU - Wymer, J. P.

AU - Simmons, Zachary

AU - McClain, C.

AU - Moxley, R. T.

PY - 1997/8/14

Y1 - 1997/8/14

N2 - Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy,- insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation in cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.

AB - Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy,- insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation in cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.

UR - http://www.scopus.com/inward/record.url?scp=0030861573&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030861573&partnerID=8YFLogxK

U2 - 10.1038/ng0897-407

DO - 10.1038/ng0897-407

M3 - Article

C2 - 9241283

AN - SCOPUS:0030861573

VL - 16

SP - 407

EP - 409

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -