Identification of a Novel Four and a Half LIM Domain 1 Mutation in a Chinese Male Presented with Hypertrophic Cardiomyopathy and Mild Skeletal Muscle Hypertrophy

Zhang, Bing-Qing; Si, Nuo; Liu, Dongfang

doi:10.4103/0366-6999.162493

Cited by 4 publications

(2 citation statements)

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“…Although associated with a large number of diseases, FHL1 mutations can be divided into 2 large groups depending on the presence or absence of reducing-bodies (RBs) on muscle biopsy specimens [2]. The site of mutation is very important, as anomalies located in the distal exons, which are responsible for the synthesis of the third and fourth LIM domains, lead to non-RBs disorders, like HCM and EDMD [2,5].…”

Section: Discussionmentioning

confidence: 99%

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy – a case report

et al. 2020

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Background Hypertrophic cardiomyopathy (HCM) is a genetic disorder mostly caused by sarcomeric gene mutations, but almost 10% of cases are attributed to inherited metabolic and neuromuscular disorders. First described in 2008 in an American-Italian family with scapuloperoneal myopathy, FHL1 gene encodes four-and-a-half LIM domains 1 proteins which are involved in sarcomere formation, assembly and biomechanical stress sensing both in cardiac and skeletal muscle, and its mutations are responsible for a large spectrum of neuromuscular disorders (mostly myopathies) and cardiac disease, represented by HCM, either isolated, or in conjunction with neurologic and skeletal muscle impairment. We thereby report a novel mutation variant in FHL1 structure, associated with HCM and type 6 Emery-Dreifuss muscular dystrophy (EDMD). Case presentation We describe the case of a 40 year old male patient, who was referred to our department for evaluation in the setting of NYHA II heart failure symptoms and was found to have HCM. The elevated muscular enzymes raised the suspicion of a neuromuscular disease. Rigid low spine and wasting of deltoidus, supraspinatus, infraspinatus and calf muscles were described by the neurological examination. Electromyography and muscle biopsy found evidence of chronic myopathy. Diagnosis work-up was completed by next-generation sequencing genetic testing which found a likely pathogenic mutation in the FHL1 gene (c.157-1G > A, hemizygous) involved in the development of X-linked EDMD type 6. Conclusion This case report highlights the importance of multimodality diagnostic approach in a patient with a neuromuscular disorder and associated hypertrophic cardiomyopathy by identifying a novel mutation variant in FHL1 gene. Raising awareness of non-sarcomeric gene mutations which can lead to HCM is fundamental, because of diagnostic and clinical risk stratification challenges.

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Section: Discussionmentioning

confidence: 99%

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy – a case report

et al. 2020

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“…Hypertrophic cardiomyopathy (HCM) mutations are largely found in sarcomeric genes, with the five most common being β-myosin heavy chain (MYH7), cardiac myosin-binding protein C (MYBC3), troponin T (TNNT2), troponin I (TNNI3), and myosin regulatory light chain 2(MYL2) (Friedrich et al 2012). Increasing evidence points to the contribution that FHL1 mutations play in HCM development and there has been effort to identify these mutations in HCM patient populations without mutations in the classically defined causal genes (Cowling et al 2011;D'Arcy et al 2015;Friedrich et al 2012;Gossios et al 2013;Hartmannova et al 2013;Knoblauch et al 2010;Zhang et al 2015) (Table 1). A study looking to identify FHL1 mutations in these HCM patient populations reported several FHL1 variants, with two of these predicted to result in a truncated FHL1 protein lacking a large portion of the C-terminus (Friedrich et al 2012).…”

Section: Fhl1 and Fhl2 Variants Are Associated With Hypertrophic Cardmentioning

confidence: 99%

Four and a half LIM domain protein signaling and cardiomyopathy

et al. 2018

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Four and a half LIM domain (FHL) protein family members, FHL1 and FHL2, are multifunctional proteins that are enriched in cardiac muscle. Although they both localize within the cardiomyocyte sarcomere (titin N2B), they have been shown to have important yet unique functions within the context of cardiac hypertrophy and disease. Studies in FHL1-deficient mice have primarily uncovered mitogen-activated protein kinase (MAPK) scaffolding functions for FHL1 as part of a novel biomechanical stretch sensor within the cardiomyocyte sarcomere, which acts as a positive regulator of pressure overload-mediated cardiac hypertrophy. New data have highlighted a novel role for the serine/threonine protein phosphatase (PP5) as a deactivator of the FHL1-based biomechanical stretch sensor, which has implications in not only cardiac hypertrophy but also heart failure. In contrast, studies in FHL2-deficient mice have primarily uncovered an opposing role for FHL2 as a negative regulator of adrenergic-mediated signaling and cardiac hypertrophy, further suggesting unique functions targeted by FHL proteins in the "stressed" cardiomyocyte. In this review, we provide current knowledge of the role of FHL1 and FHL2 in cardiac muscle as it relates to their actions in cardiac hypertrophy and cardiomyopathy. A specific focus will be to dissect the pathways and protein-protein interactions that underlie FHLs' signaling role in cardiac hypertrophy as well as provide a comprehensive list of FHL mutations linked to cardiac disease, using evidence gained from genetic mouse models and human genetic studies.

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Lumping versus splitting: How to approach defining a disease to enable accurate genomic curation

Thaxton

Goldstein

DiStefano³

et al. 2022

Cell Genomics

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Identification of a Novel Four and a Half LIM Domain 1 Mutation in a Chinese Male Presented with Hypertrophic Cardiomyopathy and Mild Skeletal Muscle Hypertrophy

Cited by 4 publications

References 5 publications

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy – a case report

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy – a case report

Four and a half LIM domain protein signaling and cardiomyopathy

Lumping versus splitting: How to approach defining a disease to enable accurate genomic curation

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