Novel Non-contiguous Duplications in the DMD Gene in Five Patients with Duchenne Muscular Dystrophy

John Hoon Rim; Sun-Mi Cho; Nae Yu; Kyung-A Lee

doi:10.3343/lmo.2015.5.3.121

Journal List > Lab Med Online > v.5(3) > 1057269

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Rim, Cho, Yu, and Lee: Novel Non-contiguous Duplications in the DMD Gene in Five Patients with Duchenne Muscular Dystrophy

Original Article

Diagnostic Genetics

Laboratory Medicine Online 2015; 5(3): 121-126.

Published online: 1 July 2015

DOI: https://doi.org/10.3343/lmo.2015.5.3.121

Novel Non-contiguous Duplications in the DMD Gene in Five Patients with Duchenne Muscular Dystrophy

John Hoon Rim, M.D.¹, Sun-Mi Cho, M.D.¹, Nae Yu, M.D.¹, Kyung-A Lee, M.D.^1,²

¹Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.

²Department of Rehabilitation, Institute of Neuromuscular Disease, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Corresponding author: Kyung-A Lee. Department of Laboratory Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 135-720, Korea. Tel: +82-2-2019-3531, Fax: +82-2-2019-4822, KAL1119@yuhs.ac

Received 5 September 2014 Revised 3 December 2014 Accepted 13 February 2015

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Muscular dystrophy is an X-linked recessive disorder caused by mutations in the DMD gene. Muscular dystrophy is classified into 2 types; Duchenne muscular dystrophy (DMD), which has severe clinical symptoms, and Becker muscular dystrophy (BMD), which has much milder clinical symptoms. Phenotypic progression to either DMD or BMD can be predicted by analyzing mutations in DMD by using the reading frame rule.

Methods

Of 88 patients with mutations in DMD, which were detected using Multiplex Ligation-dependent Probe Amplification DMD test kit (MRC-Holland, The Netherlands), medical records of 5 patients with non-contiguous duplications were reviewed. These rare non-contiguous duplications in DMD were compared with those reported previously.

Results

We identified 3 novel non-contiguous duplications in DMD that included exons 2-7 and 45-51, exons 5-37 and 50-59, and exons 52-53 and 56-61. The 5 patients with these non-contiguous duplications showed the phenotypic features of DMD. Especially, duplication of exons 52-53 and 56-61 was observed in a family, i.e., 2 DMD-affected brothers and their carrier mother.

Conclusions

Prediction of phenotypes associated with complex non-contiguous duplications by using the reading frame rule is difficult because the duplications affect the expression of DMD together. Because most patients with non-contiguous duplications showed the phenotypic features of DMD, the reading frame rule should be interpreted cautiously. This study provides important insights on the non-contiguous duplications in DMD for understanding genotype-phenotype correlations and for developing dystrophin for therapeutic purposes.

Keywords: Duchenne muscular dystrophy, DMD gene, Non-contiguous duplication, Multiplex ligation-dependent probe amplification (MLPA)

Figures and Tables

Fig. 1

Results of MLPA analysis for patient 1 (non-contiguous duplication of exons 2-7 and 45-51).

Table 1

Clinical features of the 5 patients examined in this study

Patient	Sex	Symptoms of onset/age	Age at the last follow-up	Ambulation	Cardiac involvement	Scoliosis	Chronic respiratory rehabilitation	Creatine kinase (U/L)^‡
1^*	Male	Gait disturbance/3 yr old	20 yr old	Impossible	Normal	Yes	Yes	3,063
2^*	Male	Delayed development/5 yr old	24 yr old	Impossible	Dilated cardiomyopathy	Yes	Yes	1,829
3^†	Male	Delayed language development/4 yr old	16 yr old	Impossible	Normal	Yes	Yes	1,016
4^†	Male	Delayed language development/2 yr old	14 yr old	Impossible	Mild cardiomyopathy	Yes	Yes	1,486
5^†	Female	Lower limb weakness/24 yr old	38 yr old	Possible	Normal	No	Yes	1,350

^*Family study was not performed; ^†Family members; ^‡Level of creatine kinase was measured at the time of diagnosis.

Table 2

A summary of the identified non-contiguous duplications in DMD

Patient	Phenotype	Frame of the first duplication	Frame of the second duplication	Country	Reference
P1	DMD	Exon 2-7/In frame	Exon 45-51/In frame	Korea	This study
P2	DMD	Exon 5-37/In frame	Exon 50-59/In frame	Korea	This study
P3^*	DMD	Exon 52-53/In frame	Exon 56-61/Out of frame	Korea	This study
P4^*	DMD	Exon 52-53/In frame	Exon 56-61/Out of frame	Korea	This study
P5^*	DMD carrier	Exon 52-53/In frame	Exon 56-61/Out of frame	Korea	This study
p1	DMD	Exon 45-48/In frame	Exon 54-55/In frame	Germany	Neurogenetics (2005)
p2	NA	Exon 5-19/Out of frame	Exon 38-41/In frame	Multicenter	Human Mutation (2006)
p3	NA	Exon 45-55/In frame	Exon 65-79/Out of frame	Multicenter	Human Mutation (2006)
p4	DMD	Exon 45-48/In frame	Exon 55-63/Out of frame	Japan	Journal of Human Genetics (2008)
p5^†	DMD	Exon 2-7/In frame	Exon 50-55/In frame	Spain	Journal of Neurogenetics (2008)
p6^†	DMD	Exon 2-7/In frame	Exon 50-55/In frame	Spain	Journal of Neurogenetics (2008)
p7^†	DMD carrier	Exon 2-7/In frame	Exon 50-55/In frame	Spain	Journal of Neurogenetics (2008)
p8	IMD	Exon 1/Undetermined	Exon 42-43/Out of frame	Mexico	Journal of Genetics (2014)

^*,†Family members.

Abbreviations: DMD, Duchenne muscular dystrophy; IMD, intermediate muscular dystrophy; NA, not available.

Notes

This article is available from http://www.labmedonline.org

References

1. Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991; 1:19–29.

2. Forrest SM, Cross GS, Flint T, Speer A, Robson KJ, Davies KE. Further studies of gene deletions that cause Duchenne and Becker muscular dystrophies. Genomics. 1988; 2:109–114.

3. Prior TW, Bridgeman SJ. Experience and strategy for the molecular testing of Duchenne muscular dystrophy. J Mol Diagn. 2005; 7:317–326.

4. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987; 50:509–517.

5. Hu XY, Ray PN, Murphy EG, Thompson MW, Worton RG. Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin, and phenotypegenotype correlation. Am J Hum Genet. 1990; 46:682–695.

6. Roberts RG, Bobrow M, Bentley DR. Point mutations in the dystrophin gene. Proc Natl Acad Sci U S A. 1992; 89:2331–2335.

7. Lai KK, Lo IF, Tong TM, Cheng LY, Lam ST. Detecting exon deletions and duplications of the DMD gene using Multiplex Ligation-dependent Probe Amplification (MLPA). Clin Biochem. 2006; 39:367–372.

8. Gatta V, Scarciolla O, Gaspari AR, Palka C, De Angelis MV, Di Muzio A, et al. Identification of deletions and duplications of the DMD gene in affected males and carrier females by multiple ligation probe amplification (MLPA). Hum Genet. 2005; 117:92–98.

9. Monaco AP, Bertelson CJ, Liechti-Gallati S, Moser H, Kunkel LM. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics. 1988; 2:90–95.

10. Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve. 2006; 34:135–144.

11. Tuffery-Giraud S, Béroud C, Leturcq F, Yaou RB, Hamroun D, Michel-Calemard L, et al. Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase. Hum Mutat. 2009; 30:934–945.

12. López-Hernández LB, Gómez-Díaz B, Bahena-Martínez E, Neri-Gómez T, Camacho-Molina A, Ruano-Calderón LA, et al. A novel noncontiguous duplication in the DMD gene escapes the 'reading-frame rule'. J Genet. 2014; 93:225–229.

13. Janssen B, Hartmann C, Scholz V, Jauch A, Zschocke J. MLPA analysis for the detection of deletions, duplications and complex rearrangements in the dystrophin gene: potential and pitfalls. Neurogenetics. 2005; 6:29–35.

14. Imoto N, Arinami T, Hamano K, Matsumura K, Yamada H, Hamaguchi H, et al. Topographic pattern of the rearrangement of the dystrophin gene in Japanese Duchenne muscular dystrophy. Hum Genet. 1993; 92:533–536.

15. White SJ, Aartsma-Rus A, Flanigan KM, Weiss RB, Kneppers AL, Lalic T, et al. Duplications in the DMD gene. Hum Mutat. 2006; 27:938–945.

16. Zhang Z, Takeshima Y, Awano H, Nishiyama A, Okizuka Y, Yagi M, et al. Tandem duplications of two separate fragments of the dystrophin gene in a patient with Duchenne muscular dystrophy. J Hum Genet. 2008; 53:215–219.

17. Fenollar-Cortés M, Gallego-Merlo J, Trujillo-Tiebas MJ, Lorda-Sánchez I, Ayuso C. Two non-contiguous duplications in the DMD gene in a Spanish family. J Neurogenet. 2008; 22:93–101.

18. Hu XY, Ray PN, Worton RG. Mechanisms of tandem duplication in the Duchenne muscular dystrophy gene include both homologous and nonhomologous intrachromosomal recombination. EMBO J. 1991; 10:2471–2477.

19. Lopes J, Tardieu S, Silander K, Blair I, Vandenberghe A, Palau F, et al. Homologous DNA exchanges in humans can be explained by the yeast double-strand break repair model: a study of 17p11.2 rearrangements associated with CMT1A and HNPP. Hum Mol Genet. 1999; 8:2285–2292.

20. Helderman-van den Enden AT, de Jong R, den Dunnen JT, Houwing-Duistermaat JJ, Kneppers AL, Ginjaar HB, et al. Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy. Clin Genet. 2009; 75:465–472.

21. Sommer SS. Recent human germ-line mutation: inferences from patients with hemophilia B. Trends Genet. 1995; 11:141–147.

22. Helmrich A, Ballarino M, Tora L. Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell. 2011; 44:966–977.

23. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987; 51:919–928.

TOOLS

Similar articles