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The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy

Nagai, Masashi Awano, Hiroyuki Yamamoto, Tetsushi Bo, Ryosuke Matsuo, Masafumi Iijima, Kazumoto 神戸大学

2020.10.19

概要

Background: Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease caused by mutations in the DMD gene. Dilated cardiomyopathy is the leading cause of death in DMD; therefore, further understanding of this complication is essential to reduce morbidity and mortality. Methods: A common null variant (R577X) in the ACTN3 gene, which encodes α-actinin-3, has been studied in association with muscle function in healthy individuals; however it has not yet been examined in relationship to the cardiac phenotype in DMD. In this study, we determined the ACTN3 genotype in 163 patients with DMD and examined the correlation between ACTN3 genotypes and echocardiographic findings in 77 of the 163 patients. Results: The genotypes 577RR(RR), 577RX(RX) and 577XX(XX) were identified in 13 (17%), 44 (57%) and 20 (26%) of 77 patients, respectively. We estimated cardiac involvement-free survival rate analyses using Kaplan-Meier curves. Remarkably, the left ventricular dilation (> 55 mm)-free survival rate was significantly lower in patients with the XX null genotype (P < 0.01). The XX null genotype showed a higher risk for LV dilation (hazard ratio 9.04). Conclusions: This study revealed that the ACTN3 XX null genotype was associated with a lower left ventricular dilation-free survival rate in patients with DMD. These results suggest that the ACTN3 genotype should be determined at the time of diagnosis of DMD to improve patients’ cardiac outcomes.

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a.FANTOM5, https://fantom.gsc.riken.jp/5/,

hg19.cage_peak_phase1and2combined_tpm_ann.osc.txt.gz, accecced at Feb/20/2020

b. GEO profiles, https://www.ncbi.nlm.nih.gov/geoprofiles, ID27912914, accecced at Feb/20/2020

Table 1. Clinical characteristics of ACTN3 genotypes

Participants

Initial echocardiographic examination age

8.8

9.5

9.2

(7.4 – 12.2)

(7.9 – 12.4)

(7.9-11.5)

14.7±3.8

15.6±5.1

13.6±4.2

0.28

Oral prednisolone use (%)

7 (53.9)

14 (31.8)

8 (40.0)

0.34

ACE inhibitor use (%)

6 (46.2)

19 (43.2)

11 (55.0)

0.77

Beta-blocker use (%)

6 (46.2)

16(34.0)

9 (45.0)

0.59

0.19*

(Median, inter-quartile range, years)

Final echocardiographic examination age

0.69

(Mean±SD, years)

Median age at loss of ambulation (years)

RR, Patient with wild type c.1729C (p.577R) variant in two alleles; RX, Patient with a single

nucleotide variant of C.1729C>T (p. R577X); XX, Patient with a single nucleotide variant in both

alleles. *Compared by log-rank test.

Table 2. Clinical characteristics of ACTN3 positive and null genotypes

ACTN3 positive genotype

ACTN3 null genotype

Participants

Initial echocardiographic examination age

9.3

9.15

(Median, inter-quartile range, years)

(7.8 - 12.2)

(7.9 – 11.5)

Final echocardiographic examination age

15.4±4.8

13.6±4.2

0.14

Oral prednisolone use (%)

21 (36.8)

8 (40.0)

0.80

ACE inhibitor use (%)

25 (43.9)

11 (55.0)

0.44

Beta-blocker use (%)

22 (38.6)

9 (45.0)

0.79

0.21*

0.66

(Mean±SD, years)

Median age at loss of ambulation (years)

*Compared by log-rank test

Supplementary Table 1

List of identified mutations the DMD gene and polymorphisms in the ACTN3 gene.

KUCG

ACTN3

DMD mutation

Predicted effect of DMD mutation

c.6283C>T

nonsense mutation in exon 7

145

c.8218-?_8390+?dup

duplication of exon 56

147

c.6423C>A

nonsense mutation in exon 44

170

c.7661-?_8027+?del

deletion of exons 53 to 54

181

c.6615-?_7098+?del

deletion of exons 46 to 48

201

c.531-?_4071+?del

deletion of exons 7 to 29

202

c.6615-?_7542+?del

deletion of exons 46 to 51

213

c.6291-?_6438+?del

deletion of exon 44

214

c.6439-?_7309+?del

deletion of exons 45 to 50

225

c.5899C>T

nonsense mutation in exon 41

245

c.3959delC

1bp deletion in exon 29

258

c.6439-?_7660+?del

deletion of exons 45 to 52

263

c.6291-?_6438+?del

deletion of exon 44

277

c.1773delA

1bp deletion in exon 15

294

c.2168+1G>C

splicing mutation at exon 17

327

c.6615-?_7912+?del

deletion of exons 46 to 47

342

c.7654delG

1bp deletion in exon 52

348

c.6615-?_7200+?del

deletion of exons 46 to 49

376

c.2169-?_5326+?del

deletion of exons 18 to 37

377

c.1062G>A

nonsense mutation in exon 10

382

c.94-?_2169+?del

deletion of exons 3 to 17

394

c.7661-?_8027+?del

deletion of exons 53 to 54

395

c.7543-?_7660+?del

deletion of exon 52

399

c.6615-?_7098+?del

deletion of exons 46 to 48

427

c.6615-?_7098+?del

deletion of exons 46 to 48

434

c.3347_3350delAGAA

4bp deletion in exon 25

435

c.7310-?_7542+?del

deletion of exon 51

436

c.5561delT

1bp deletion in exon 39

Number

polymorphism

441

c.10498_10499delAG

2bp deletion in exon 74

447

c.8218-?_9224+?dup

duplication of exons 56 to 62

449

c.961-?_1602+?del

deletion of exons 10 to 13

456

c.7817G>A

nonsense mutation in exon 53

472

c.2804-?_6438+?dup

duplication of exons 22 to 44

474

c.6913-?_7309+?del

deletion of exons 48 to 50

478

c.9913G>T

nonsense mutation in exon 68

501

c.5899C>T

nonsense mutation in exon 41

505

c.4729delC

1bp deletion in exon 34

512

c.6613dupA

1bp insertion in exon 45

559

c.6805C>T

nonsense mutation in exon 47

571

c.355C>T

nonsense mutation in exon 5

577

c.5551C>T

nonsense mutation in exon 39

581

c.6615-?_7542+?del

deletion of exons 46 to 51

603

c.7310-?_9084+?dup

duplication of exons 51 to 60

610

c.6439-?_7309+?del

deletion of exons 48 to 50

623

c.6439-?_6614+?del

deletion of exon 45

630

c.6291-?_6912+?del

deletion of exons 44 to 47

643

c.8460G>A

nonsense mutation in exon 57

651

c.5899C>T

nonsense mutation in exon 41

656

c.6913-?_7660+?del

deletion of exons 48 to 52

664

c.650-?_1602+?del

deletion of exons 8 to 13

681

c.7099-?_7660+?del

deletion of exons 49 to 52

689

c.650-?_3276+?del

deletion of exons 8 to 24

708

c.94-?_649+?del

duplication of exons 10 to 11

712

c.1329_1331+5delCAAGTAAG

splicing mutation at exon 11

726

c.783dupT

1bp insertion in exon 8

740

c.961-?_1331+?dup

duplication of exons 10 to 11

763

c.6291-?_6438+?del

deletion of exon 44

767

c.650-?_1992+?dup

duplication of exons 8 to 16

791

c.7543-?_7660+?del

deletion of exon 52

795

c.4536_4540delGAGTG

5bp deletion in exon 33

809

c.2677C>T

nonsense mutation in exon21

810

c.650-?_2292+?del

deletion of exons 8 to 18

815

c.961-?_2169+?del

deletion of exons 10 to 17

818

c.3908_3909delCT

2bp deletion in exon 28

847

c.2419C>T

nonsense mutation in exon20

851

c.650-?_2292+?del

deletion of exons 8 to 18

857

c.9807+2714C>T

deep intronic mutation in intron 67

865

c.6615-?_6912+?del

deletion of exons 46 to 47

877

c.4414C>T

nonsense mutation in exon32

879

c.7657C>T

nonsense mutation in exon52

898

c.10108 C>T

nonsense mutation in exon70

907

c.724C>T

nonsense mutation in exon8

915

c.6615-?_7872+?del

deletion of exons 46 to 53

921

c.9851G>A

nonsense mutation in exon68

923

c.7780C>T

nonsense mutation in exon53

926

c.6439-?_6614+?del

deletion of exon 45

939

c.6291-?_6438+?del

deletion of exon 44

KUCG; Kobe University Clinical Genetics

Highlights

ACTN3 genotype is a genetic modifier for Duchene muscular dystrophy

ACTN3 genotype with risk of dilated cardiomyopathy in patients was studied

ACTN3 577XX null genotype has low left ventricular dilation-free survival rate

ACTN3 577XX null genotype is a risk factor for left ventricular dilation

...

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The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy

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The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy

概要

この論文で使われている画像

関連論文

Systematic Review of Clinical Characteristics and Genotype-Phenotype Correlation in LAMB2-Associated Disease

Molecular genetic study of the FMR1 CGG repeat configurations in the Japanese population and patients with Fragile X-Associated Tremor/Ataxia Syndrome

Associations between Left Ventricular Cavity Size and Cardiac Function and Overload Determined by Natriuretic Peptide Levels and a Covariance Structure Analysis.

Circulatory C-type natriuretic peptide reduces mucopolysaccharidosis-associated craniofacial hypoplasia in vivo

Catheter Ablation of Ventricular Tachycardia Associated with Hypertrophic Cardiomyopathy: Substrate Characterization and Ablation Outcome According to Clinical Subtypes.

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