Size of the Unstable CTG Repeat Sequence in Relation to Phenotype and Parental Transmission in Myotonic Dystrophy

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1993 Jun 1

PMID 8503448

Citations 115

Authors

H G Harley

S A Rundle

J C MacMillan

J Myring

J D Brook

S Crow

W Reardon

I Fenton

D J Shaw

P S Harper

Affiliations

Soon will be listed here.

Abstract

A clinical and molecular analysis of 439 individuals affected with myotonic dystrophy, from 101 kindreds, has shown that the size of the unstable CTG repeat detected in nearly all cases of myotonic dystrophy is related both to age at onset of the disorder and to the severity of the phenotype. The largest repeat sizes (1.5-6.0 kb) are seen in patients with congenital myotonic dystrophy, while the minimally affected patients have repeat sizes of < 0.5 kb. Comparison of parent-child pairs has shown that most offspring have an earlier age at onset and a larger repeat size than their parents, with only 4 of 182 showing a definite decrease in repeat size, accompanied by a later age at onset or less severe phenotype. Increase in repeat size from parent to child is similar for both paternal and maternal transmissions when the increase is expressed as a proportion of the parental repeat size. Analysis of congenitally affected cases shows not only that they have, on average, the largest repeat sizes but also that their mothers have larger mean repeat sizes, supporting previous suggestions that a maternal effect is involved in the pathogenesis of this form of the disorder.

Citing Articles

RNA mis-splicing in children with congenital myotonic dystrophy is associated with physical function.

Hartman J, Ikegami K, Provenzano M, Bates K, Butler A, Jones A Ann Clin Transl Neurol. 2024; 11(12):3175-3191.

PMID: 39450929 PMC: 11651218. DOI: 10.1002/acn3.52224.

Small molecules modulating RNA splicing: a review of targets and future perspectives.

Bouton L, Ecoutin A, Malard F, Campagne S RSC Med Chem. 2024; 15(4):1109-1126.

PMID: 38665842 PMC: 11042171. DOI: 10.1039/d3md00685a.

Neurobehavioral Phenotype of Children With Congenital Myotonic Dystrophy.

Patel N, Berggren K, Hung M, Bates K, Dixon M, Bax K Neurology. 2024; 102(5):e208115.

PMID: 38359368 PMC: 11384658. DOI: 10.1212/WNL.0000000000208115.

Transcriptome-Wide Studies of RNA-Targeted Small Molecules Provide a Simple and Selective r(CUG) Degrader in Myotonic Dystrophy.

Gibaut Q, Bush J, Tong Y, Baisden J, Taghavi A, Olafson H ACS Cent Sci. 2023; 9(7):1342-1353.

PMID: 37521782 PMC: 10375898. DOI: 10.1021/acscentsci.2c01223.

Mbnl2 loss alters novel context processing and impairs object recognition memory.

Khandelwal A, Cushman J, Choi J, Zhuravka I, Rajbhandari A, Valiulahi P iScience. 2023; 26(5):106732.

PMID: 37216102 PMC: 10193234. DOI: 10.1016/j.isci.2023.106732.

References

Mathieu J, De Braekeleer M, Prevost C . Genealogical reconstruction of myotonic dystrophy in the Saguenay-Lac-Saint-Jean area (Quebec, Canada). Neurology. 1990; 40(5):839-42. DOI: 10.1212/wnl.40.5.839. View

Howeler C, BUSCH H, Geraedts J, Niermeijer M, Staal A . Anticipation in myotonic dystrophy: fact or fiction?. Brain. 1989; 112 ( Pt 3):779-97. DOI: 10.1093/brain/112.3.779. View

Yu S, Pritchard M, Kremer E, Lynch M, Nancarrow J, Baker E . Fragile X genotype characterized by an unstable region of DNA. Science. 1991; 252(5009):1179-81. DOI: 10.1126/science.252.5009.1179. View

Koch M, Grimm T, Harley H, Harper P . Genetic risks for children of women with myotonic dystrophy. Am J Hum Genet. 1991; 48(6):1084-91. PMC: 1683098. View

Harley H, Brook J, Floyd J, Rundle S, Crow S, Walsh K . Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker. Am J Hum Genet. 1991; 49(1):68-75. PMC: 1683213. View

Brunner H, Smeets H, Nillesen W, van Oost B, van den Biezenbos J, Joosten E . Myotonic dystrophy. Predictive value of normal results on clinical examination. Brain. 1991; 114 ( Pt 5):2303-11. DOI: 10.1093/brain/114.5.2303. View

Brook J, McCurrach M, Harley H, Buckler A, Church D, Aburatani H . Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992; 68(4):799-808. DOI: 10.1016/0092-8674(92)90154-5. View

Harley H, Brook J, Rundle S, Crow S, Reardon W, Buckler A . Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature. 1992; 355(6360):545-6. DOI: 10.1038/355545a0. View

Buxton J, Shelbourne P, Davies J, Jones C, Van Tongeren T, Aslanidis C . Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature. 1992; 355(6360):547-8. DOI: 10.1038/355547a0. View

10.

Aslanidis C, Jansen G, Amemiya C, Shutler G, Mahadevan M, Tsilfidis C . Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature. 1992; 355(6360):548-51. DOI: 10.1038/355548a0. View

11.

Yamagata H, Miki T, Ogihara T, Nakagawa M, Higuchi I, Osame M . Expansion of unstable DNA region in Japanese myotonic dystrophy patients. Lancet. 1992; 339(8794):692. DOI: 10.1016/0140-6736(92)90862-w. View

12.

Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G . Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science. 1992; 255(5049):1253-5. DOI: 10.1126/science.1546325. View

13.

Fu Y, Pizzuti A, Fenwick Jr R, King J, Rajnarayan S, Dunne P . An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992; 255(5049):1256-8. DOI: 10.1126/science.1546326. View

14.

Harley H, Rundle S, Reardon W, Myring J, Crow S, Brook J . Unstable DNA sequence in myotonic dystrophy. Lancet. 1992; 339(8802):1125-8. DOI: 10.1016/0140-6736(92)90729-m. View

15.

Harper P, Harley H, Reardon W, Shaw D . Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet. 1992; 51(1):10-6. PMC: 1682874. View

16.

Reardon W, FLOYD J, Myring J, Lazarou L, Meredith A, Harper P . Five years experience of predictive testing for myotonic dystrophy using linked DNA markers. Am J Med Genet. 1992; 43(6):1006-11. DOI: 10.1002/ajmg.1320430618. View

17.

Reardon W, Harley H, Brook J, Rundle S, Crow S, Harper P . Minimal expression of myotonic dystrophy: a clinical and molecular analysis. J Med Genet. 1992; 29(11):770-3. PMC: 1016168. DOI: 10.1136/jmg.29.11.770. View

18.

Richards R, Holman K, Friend K, Kremer E, Hillen D, Staples A . Evidence of founder chromosomes in fragile X syndrome. Nat Genet. 1992; 1(4):257-60. DOI: 10.1038/ng0792-257. View

19.

Tsilfidis C, Mackenzie A, Mettler G, Barcelo J, Korneluk R . Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nat Genet. 1992; 1(3):192-5. DOI: 10.1038/ng0692-192. View

20.

Oberle I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer A . Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991; 252(5009):1097-102. DOI: 10.1126/science.252.5009.1097. View