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Fukutin gene mutations that cause left ventricular noncompaction
International Journal of Cardiology 222 (2016) 727–729
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Fukutin gene mutations that cause left ventricular noncompaction Eisuke Amiya a,⁎, Hiroyuki Morita a,⁎, Masaru Hatano a,f, Daisuke Nitta a, Yumiko Hosoya a, Hisataka Maki a, Yoshihiro Motozawa a, Naoko Sato d, Hiroyuki Ishiura d, Satoe Numakura e, Yukako Shintani c, Koichiro Kinugawa b, Norifumi Takeda a, Jun Shimizu d, Shoji Tsuji d, Issei Komuro a a
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan Second Department of Internal Medicine, University of Toyama, Japan Department of Pathology, Graduate School of Medicine, University of Tokyo, Japan d Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan e Department of Pathology, Mitsui Memorial Hospital, Japan f Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 12 June 2016 Accepted 2 August 2016 Available online 3 August 2016 Keywords: Left ventricular noncompaction Fukutin Heart failure Muscular dystrophy
Left ventricular noncompaction (LVNC) is a clinicopathologic entity, characterized by a pattern of prominent trabecular meshwork and deep intertrabecular recesses communicating with the left ventricular cavity [1]. The etiology of LVNC is highly heterogeneous, including isolated non-syndromic causes from single gene mutations and systemic syndromic causes associated with chromosomal anomalies, genetic disorders, and neuromuscular diseases. Here we report a 26-year-old man who was suspected as having Becker muscular dystrophy, presenting with congestive heart failure and sudden cardiac death due to LVNC. A postmortem pathological examination and genetic analysis revealed that this patient had an atypical form of Fukuyama congenital muscular dystrophy. The genetic analysis was approved by the ethics committee of the University of Tokyo (G-2249, G-1396). Written informed consent was obtained after providing a detailed explanation of the purpose for this analysis. The investigation conforms to the principles outlined in the Declaration of Helsinki. A 26-year-old male was hospitalized due to the exacerbation of heart failure. He was born after an uneventful pregnancy to a healthy mother, and his early development was normal. At three years of age, the increase in creatine kinase (CK) level led to the suspicion of Becker muscu⁎ Corresponding authors at: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail addresses: [email protected] (E. Amiya), [email protected] (H. Morita).
http://dx.doi.org/10.1016/j.ijcard.2016.08.011 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
lar dystrophy. However, there was no muscle weakness. At age of 13 years, he was admitted to the hospital because of his electrocardiographic abnormalities, and echocardiography revealed the reduced ejection fraction (30%) and characteristics of left ventricular noncompaction (LVNC). An angiotensin II receptor blocker and a beta blocker were administered. However, his left ventricle gradually dilated and his systolic function declined. At the age of 26, he was hospitalized because of an exacerbation of heart failure. At the time of hospitalization, there was no mental retardation, ocular abnormality or muscle weakness. His laboratory data revealed a moderate increase in CK level (746 U/L), and there was no development of calf hypertrophy. The echocardiography identified a severe dilation (left ventricular diastolic diameter: 77 mm) of the four chambers and severely impaired left ventricular function (ejection fraction: 17%) with deep recesses extending to the inner half of the ventricular wall (Fig. 1A). The brain natriuretic peptide was markedly increased (1987.7 pg/mL), and his transaminases were also increased from the baseline due to liver congestion. The support of catecholamine temporarily relieved his heart failure. However, during treatment, his hemodynamics suddenly collapsed and the intra-aortic balloon pump and percutaneous cardiopulmonary support did not reverse his hemodynamic depression. He died on the 35th day of hospitalization. In an autopsy study, there were no abnormalities of vertebrae, and no skeletal muscles with fatty degeneration. In the lingual muscle, there was an irregular arrangement of muscle fiber and a regional necrotic area, whereas the necrotic lesion was not detected in any of the other skeletal muscles. His heart weighed 447 g, showed dilation of the biventricular cavity and prominent trabeculations and invaginations in the left ventricle (Fig. 1B, C). The recesses are within the inner half of the myocardium, which met the criteria of LVNC. Histologically, there was extensive interstitial fibrosis, irregular arrangement of the muscle fibers, and anisochromacy (Fig. 1D). According to a genetic study of muscular dystrophy, no deletion or duplication of the DMD exons was found in the multiplex ligationdependent probe amplification (MLPA) analysis. A direct sequencing analysis of DMD and LMNA did not reveal any significant variant considered to function as a causal factor. On the other hand, a missense variant (c.536GNC, p.Arg179Thr) in FKTN was detected in a heterozygous mode (Fig. 2A). This variant is not common in the public genomic databases
728
Correspondence
Fig. 1. A: An echocardiographic four-chambered view of the patient's heart demonstrated the increased trabeculation and intertrabecular recesses around the apex of the left ventricle. B: Macroscopic analysis during the autopsy revealed that marked dilation with prominent trabeculations and invaginations of his left ventricle. C: Microscopic analysis of the endocardial surface by Elastica van Gieson stain. It revealed a polypoid pattern of trabecula with invaginated recesses. There is a prominent fibrous band separating the spongy from the compact myocardium. The recesses are within the inner half of the myocardium. D: Microscopic analysis of endomyocardial tissue in the compact myocardium demonstrated myocyte derangement and anisonucleosis with mild interstitial fibrosis. E–G: An immunohistochemical study of the skeletal muscle in biceps brachii muscle. E: Hematoxylin and eosin staining; F: The staining of β-dystroglycan using monoclonal antibodies shows that β-dystroglycan is present at the sarcolemma of all muscle fibers; G: Immunohistochemical analysis using a monoclonal antibody that recognizes the heavily glycosylated form of α-dystroglycan, and exhibited reduced sarcolemmal staining.
A Control His
Glu
Arg
Ser
Gly
His
Glu
Arg Thr
Ser
Gly
Patient
B a) Non-insertion allele Insertion allele
5-TGTGCAATTTTCTAGTTCCATGTT-3’
5’-TAGGAGACAACTGCTTAACC-3’
NLF
NLR ATTTGCTT
AAGAAAAA
3-kb insertion A AAAAA AA AAGAAAAA
InsF 5-TTAAACAGATGCTTGAAGGC-3’
NLR 5’-TAGGAGACAACTGCTTAACC-3’
b) Non-insertion allele
Insertion allele
Fig. 2. A: A missense mutation in the FKTN gene was identified in this case. Nucleotide sequences are shown along with the predicted amino acid sequences. An arrow indicates a mutation, resulting in a change from AGG (Arg) to ACG (Thr) (displayed in bold). B: a) A schematic representation of the PCR-based methods for detecting the 3-kb insertion sequence in the FKTN gene. One primer pair of InsF and NLR bridges the normal and insertion sequence, resulting in the amplification of a 400-bp product. Another primer pair of NLF and NLR generates a 269bp product from the normal FKTN sequence. b) Direct sequencing of each of the PCR-products above.
Correspondence
(dbSNP (http://www.ncbi.nlm.nih.gov/SNP/), Exome Sequencing Project (ESP) (http://evs.gs.washington.edu/EVS/). This patient is also heterozygote with a 3-kb retrotransposon insertion in FKTN (Fig. 2B). Because his healthy mother had a 3-kb retrotransposon insertion without the missense p.Arg179Thr mutation, compound heterozygosity of the mutations in FKTN was confirmed in the patient. To certificate the diagnosis of the fukutinopathy in which FKTN contributes to the glycosylation of α-dystroglycan(DG), immunohistochemical analysis of DG was performed on the skeletal muscle samples. The immunoreaction of α-DG (VIA4-1) (sc53986, Santa Cruz Biotechnology, Dallas, USA), which recognizes the heavily glycosylated form of α-DG, demonstrated a reduction in the sarcolemmal staining. However, the antibody for β-DG (NCL-b-DG, Novocastra Laboratories Ltd., Newcastle upon Tyne, UK) exhibited well-preserved membrane staining (Fig. 1E–G). From these findings the diagnosis of fukutinopathy was confirmed. In Japanese patients with Fukuyama congenital muscular dystrophy, the 3-kb retrotransposon insertion of FKTN is observed in either a heterozygous or homozygous manner, which is thought to be a founder mutation [2,3]. Variable mutations in the non-insertion allele may be related to variable clinical manifestations and the variable severity of fukutinopathy [4]. To date [5,6], three types of FKTN missense mutations: 1) Cys101Phe; 2) Arg179Thr; and 3) Gln358Pro were reported to cause dilated cardiomyopathy (DCM) when accompanied by a 3-kb retrotransposon insertion in a compound heterozygous manner. The mutations identified in the current case were reported to be associated with DCM with mild skeletal muscle involvement; however, it had been unknown whether it can also exhibit the clinicopathological pattern of LVNC. In DCM patients with or without the manifestation of skeletal muscle weakness, muscular dystrophy should be considered as a differential diagnosis of cardiomyopathy. In conjunction with DCM, LVNC is prevalent in patients with Duchenne/Becker muscular dystrophy [7]. Similarly, this case demonstrated that the identical mutations with those of DCM complicated with fukutinopathy could also cause LVNC. In addition, to our knowledge, this is the first report of LVNC inherited as an autosomal recessive genetic trait. The prevalence and pattern of cardiac involvement in fukutinopathy (cardiofukutinopathy) are unknown.
729
However, our findings indicate that LVNC and DCM are thought to be part of a diverse spectrum of cardiac morphologies caused by fukutin gene defects, similar to sarcomere protein gene defects [8]. Further studies are warranted to clarify which genetic mutations likely cause LVNC in the patients with a broad range of muscular dystrophy.
Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] F. Ichida, Left ventricular noncompaction, Circ. J. 73 (2009) 19–26. [2] K. Kobayashi, Y. Nakahori, M. Miyake, K. Matsumura, E. Kondo-Iida, Y. Nomura, M. Segawa, M. Yoshioka, K. Saito, M. Osawa, K. Hamano, Y. Sakakihara, I. Nonaka, Y. Nakagome, I. Kanazawa, Y. Nakamura, K. Tokunaga, T. Toda, An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy, Nature 394 (1998) 388–392. [3] M. Watanabe, K. Kobayashi, F. Jin, K.S. Park, T. Yamada, K. Tokunaga, T. Toda, Founder SVA retrotransposal insertion in Fukuyama-type congenital muscular dystrophy and its origin in Japanese and Northeast Asian populations, Am. J. Med. Genet. A 138 (2005) 344–348. [4] E. Kondo-Iida, K. Kobayashi, M. Watanabe, J. Sasaki, T. Kumagai, H. Koide, K. Saito, M. Osawa, Y. Nakamura, T. Toda, Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD), Hum. Mol. Genet. 8 (1999) 2303–2309. [5] T. Murakami, Y.K. Hayashi, S. Noguchi, M. Ogawa, I. Nonaka, Y. Tanabe, M. Ogino, F. Takada, M. Eriguchi, N. Kotooka, K.P. Campbell, M. Osawa, I. Nishino, Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness, Ann. Neurol. 60 (2006) 597–602. [6] T. Arimura, Y.K. Hayashi, T. Murakami, Y. Oya, S. Funabe, E. Arikawa-Hirasawa, N. Hattori, I. Nishino, A. Kimura, Mutational analysis of fukutin gene in dilated cardiomyopathy and hypertrophic cardiomyopathy, Circ. J. 73 (2009) 158–161. [7] K. Kimura, K. Takenaka, A. Ebihara, K. Uno, H. Morita, T. Nakajima, T. Ozawa, I. Aida, Y. Yonemochi, S. Higuchi, Y. Motoyoshi, T. Mikata, I. Uchida, T. Ishihara, T. Komori, R. Kitao, T. Nagata, S. Takeda, Y. Yatomi, R. Nagai, I. Komuro, Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy— prospective multicenter cohort study, Int. J. Cardiol. 168 (2013) 1900–1904. [8] S. Klaassen, S. Probst, E. Oechslin, B. Gerull, G. Krings, P. Schuler, M. Greutmann, D. Hürlimann, M. Yegitbasi, L. Pons, M. Gramlich, J.D. Drenckhahn, A. Heuser, F. Berger, R. Jenni, L. Thierfelder, Mutations in sarcomere protein genes in left ventricular noncompaction, Circulation 117 (2008) 2893–2901.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Fukutin gene mutations that cause left ventricular noncompaction Eisuke Amiya a,⁎, Hiroyuki Morita a,⁎, Masaru Hatano a,f, Daisuke Nitta a, Yumiko Hosoya a, Hisataka Maki a, Yoshihiro Motozawa a, Naoko Sato d, Hiroyuki Ishiura d, Satoe Numakura e, Yukako Shintani c, Koichiro Kinugawa b, Norifumi Takeda a, Jun Shimizu d, Shoji Tsuji d, Issei Komuro a a
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan Second Department of Internal Medicine, University of Toyama, Japan Department of Pathology, Graduate School of Medicine, University of Tokyo, Japan d Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan e Department of Pathology, Mitsui Memorial Hospital, Japan f Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 12 June 2016 Accepted 2 August 2016 Available online 3 August 2016 Keywords: Left ventricular noncompaction Fukutin Heart failure Muscular dystrophy
Left ventricular noncompaction (LVNC) is a clinicopathologic entity, characterized by a pattern of prominent trabecular meshwork and deep intertrabecular recesses communicating with the left ventricular cavity [1]. The etiology of LVNC is highly heterogeneous, including isolated non-syndromic causes from single gene mutations and systemic syndromic causes associated with chromosomal anomalies, genetic disorders, and neuromuscular diseases. Here we report a 26-year-old man who was suspected as having Becker muscular dystrophy, presenting with congestive heart failure and sudden cardiac death due to LVNC. A postmortem pathological examination and genetic analysis revealed that this patient had an atypical form of Fukuyama congenital muscular dystrophy. The genetic analysis was approved by the ethics committee of the University of Tokyo (G-2249, G-1396). Written informed consent was obtained after providing a detailed explanation of the purpose for this analysis. The investigation conforms to the principles outlined in the Declaration of Helsinki. A 26-year-old male was hospitalized due to the exacerbation of heart failure. He was born after an uneventful pregnancy to a healthy mother, and his early development was normal. At three years of age, the increase in creatine kinase (CK) level led to the suspicion of Becker muscu⁎ Corresponding authors at: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail addresses: [email protected] (E. Amiya), [email protected] (H. Morita).
http://dx.doi.org/10.1016/j.ijcard.2016.08.011 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
lar dystrophy. However, there was no muscle weakness. At age of 13 years, he was admitted to the hospital because of his electrocardiographic abnormalities, and echocardiography revealed the reduced ejection fraction (30%) and characteristics of left ventricular noncompaction (LVNC). An angiotensin II receptor blocker and a beta blocker were administered. However, his left ventricle gradually dilated and his systolic function declined. At the age of 26, he was hospitalized because of an exacerbation of heart failure. At the time of hospitalization, there was no mental retardation, ocular abnormality or muscle weakness. His laboratory data revealed a moderate increase in CK level (746 U/L), and there was no development of calf hypertrophy. The echocardiography identified a severe dilation (left ventricular diastolic diameter: 77 mm) of the four chambers and severely impaired left ventricular function (ejection fraction: 17%) with deep recesses extending to the inner half of the ventricular wall (Fig. 1A). The brain natriuretic peptide was markedly increased (1987.7 pg/mL), and his transaminases were also increased from the baseline due to liver congestion. The support of catecholamine temporarily relieved his heart failure. However, during treatment, his hemodynamics suddenly collapsed and the intra-aortic balloon pump and percutaneous cardiopulmonary support did not reverse his hemodynamic depression. He died on the 35th day of hospitalization. In an autopsy study, there were no abnormalities of vertebrae, and no skeletal muscles with fatty degeneration. In the lingual muscle, there was an irregular arrangement of muscle fiber and a regional necrotic area, whereas the necrotic lesion was not detected in any of the other skeletal muscles. His heart weighed 447 g, showed dilation of the biventricular cavity and prominent trabeculations and invaginations in the left ventricle (Fig. 1B, C). The recesses are within the inner half of the myocardium, which met the criteria of LVNC. Histologically, there was extensive interstitial fibrosis, irregular arrangement of the muscle fibers, and anisochromacy (Fig. 1D). According to a genetic study of muscular dystrophy, no deletion or duplication of the DMD exons was found in the multiplex ligationdependent probe amplification (MLPA) analysis. A direct sequencing analysis of DMD and LMNA did not reveal any significant variant considered to function as a causal factor. On the other hand, a missense variant (c.536GNC, p.Arg179Thr) in FKTN was detected in a heterozygous mode (Fig. 2A). This variant is not common in the public genomic databases
728
Correspondence
Fig. 1. A: An echocardiographic four-chambered view of the patient's heart demonstrated the increased trabeculation and intertrabecular recesses around the apex of the left ventricle. B: Macroscopic analysis during the autopsy revealed that marked dilation with prominent trabeculations and invaginations of his left ventricle. C: Microscopic analysis of the endocardial surface by Elastica van Gieson stain. It revealed a polypoid pattern of trabecula with invaginated recesses. There is a prominent fibrous band separating the spongy from the compact myocardium. The recesses are within the inner half of the myocardium. D: Microscopic analysis of endomyocardial tissue in the compact myocardium demonstrated myocyte derangement and anisonucleosis with mild interstitial fibrosis. E–G: An immunohistochemical study of the skeletal muscle in biceps brachii muscle. E: Hematoxylin and eosin staining; F: The staining of β-dystroglycan using monoclonal antibodies shows that β-dystroglycan is present at the sarcolemma of all muscle fibers; G: Immunohistochemical analysis using a monoclonal antibody that recognizes the heavily glycosylated form of α-dystroglycan, and exhibited reduced sarcolemmal staining.
A Control His
Glu
Arg
Ser
Gly
His
Glu
Arg Thr
Ser
Gly
Patient
B a) Non-insertion allele Insertion allele
5-TGTGCAATTTTCTAGTTCCATGTT-3’
5’-TAGGAGACAACTGCTTAACC-3’
NLF
NLR ATTTGCTT
AAGAAAAA
3-kb insertion A AAAAA AA AAGAAAAA
InsF 5-TTAAACAGATGCTTGAAGGC-3’
NLR 5’-TAGGAGACAACTGCTTAACC-3’
b) Non-insertion allele
Insertion allele
Fig. 2. A: A missense mutation in the FKTN gene was identified in this case. Nucleotide sequences are shown along with the predicted amino acid sequences. An arrow indicates a mutation, resulting in a change from AGG (Arg) to ACG (Thr) (displayed in bold). B: a) A schematic representation of the PCR-based methods for detecting the 3-kb insertion sequence in the FKTN gene. One primer pair of InsF and NLR bridges the normal and insertion sequence, resulting in the amplification of a 400-bp product. Another primer pair of NLF and NLR generates a 269bp product from the normal FKTN sequence. b) Direct sequencing of each of the PCR-products above.
Correspondence
(dbSNP (http://www.ncbi.nlm.nih.gov/SNP/), Exome Sequencing Project (ESP) (http://evs.gs.washington.edu/EVS/). This patient is also heterozygote with a 3-kb retrotransposon insertion in FKTN (Fig. 2B). Because his healthy mother had a 3-kb retrotransposon insertion without the missense p.Arg179Thr mutation, compound heterozygosity of the mutations in FKTN was confirmed in the patient. To certificate the diagnosis of the fukutinopathy in which FKTN contributes to the glycosylation of α-dystroglycan(DG), immunohistochemical analysis of DG was performed on the skeletal muscle samples. The immunoreaction of α-DG (VIA4-1) (sc53986, Santa Cruz Biotechnology, Dallas, USA), which recognizes the heavily glycosylated form of α-DG, demonstrated a reduction in the sarcolemmal staining. However, the antibody for β-DG (NCL-b-DG, Novocastra Laboratories Ltd., Newcastle upon Tyne, UK) exhibited well-preserved membrane staining (Fig. 1E–G). From these findings the diagnosis of fukutinopathy was confirmed. In Japanese patients with Fukuyama congenital muscular dystrophy, the 3-kb retrotransposon insertion of FKTN is observed in either a heterozygous or homozygous manner, which is thought to be a founder mutation [2,3]. Variable mutations in the non-insertion allele may be related to variable clinical manifestations and the variable severity of fukutinopathy [4]. To date [5,6], three types of FKTN missense mutations: 1) Cys101Phe; 2) Arg179Thr; and 3) Gln358Pro were reported to cause dilated cardiomyopathy (DCM) when accompanied by a 3-kb retrotransposon insertion in a compound heterozygous manner. The mutations identified in the current case were reported to be associated with DCM with mild skeletal muscle involvement; however, it had been unknown whether it can also exhibit the clinicopathological pattern of LVNC. In DCM patients with or without the manifestation of skeletal muscle weakness, muscular dystrophy should be considered as a differential diagnosis of cardiomyopathy. In conjunction with DCM, LVNC is prevalent in patients with Duchenne/Becker muscular dystrophy [7]. Similarly, this case demonstrated that the identical mutations with those of DCM complicated with fukutinopathy could also cause LVNC. In addition, to our knowledge, this is the first report of LVNC inherited as an autosomal recessive genetic trait. The prevalence and pattern of cardiac involvement in fukutinopathy (cardiofukutinopathy) are unknown.
729
However, our findings indicate that LVNC and DCM are thought to be part of a diverse spectrum of cardiac morphologies caused by fukutin gene defects, similar to sarcomere protein gene defects [8]. Further studies are warranted to clarify which genetic mutations likely cause LVNC in the patients with a broad range of muscular dystrophy.
Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] F. Ichida, Left ventricular noncompaction, Circ. J. 73 (2009) 19–26. [2] K. Kobayashi, Y. Nakahori, M. Miyake, K. Matsumura, E. Kondo-Iida, Y. Nomura, M. Segawa, M. Yoshioka, K. Saito, M. Osawa, K. Hamano, Y. Sakakihara, I. Nonaka, Y. Nakagome, I. Kanazawa, Y. Nakamura, K. Tokunaga, T. Toda, An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy, Nature 394 (1998) 388–392. [3] M. Watanabe, K. Kobayashi, F. Jin, K.S. Park, T. Yamada, K. Tokunaga, T. Toda, Founder SVA retrotransposal insertion in Fukuyama-type congenital muscular dystrophy and its origin in Japanese and Northeast Asian populations, Am. J. Med. Genet. A 138 (2005) 344–348. [4] E. Kondo-Iida, K. Kobayashi, M. Watanabe, J. Sasaki, T. Kumagai, H. Koide, K. Saito, M. Osawa, Y. Nakamura, T. Toda, Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD), Hum. Mol. Genet. 8 (1999) 2303–2309. [5] T. Murakami, Y.K. Hayashi, S. Noguchi, M. Ogawa, I. Nonaka, Y. Tanabe, M. Ogino, F. Takada, M. Eriguchi, N. Kotooka, K.P. Campbell, M. Osawa, I. Nishino, Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness, Ann. Neurol. 60 (2006) 597–602. [6] T. Arimura, Y.K. Hayashi, T. Murakami, Y. Oya, S. Funabe, E. Arikawa-Hirasawa, N. Hattori, I. Nishino, A. Kimura, Mutational analysis of fukutin gene in dilated cardiomyopathy and hypertrophic cardiomyopathy, Circ. J. 73 (2009) 158–161. [7] K. Kimura, K. Takenaka, A. Ebihara, K. Uno, H. Morita, T. Nakajima, T. Ozawa, I. Aida, Y. Yonemochi, S. Higuchi, Y. Motoyoshi, T. Mikata, I. Uchida, T. Ishihara, T. Komori, R. Kitao, T. Nagata, S. Takeda, Y. Yatomi, R. Nagai, I. Komuro, Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy— prospective multicenter cohort study, Int. J. Cardiol. 168 (2013) 1900–1904. [8] S. Klaassen, S. Probst, E. Oechslin, B. Gerull, G. Krings, P. Schuler, M. Greutmann, D. Hürlimann, M. Yegitbasi, L. Pons, M. Gramlich, J.D. Drenckhahn, A. Heuser, F. Berger, R. Jenni, L. Thierfelder, Mutations in sarcomere protein genes in left ventricular noncompaction, Circulation 117 (2008) 2893–2901.