Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES

doi:10.1016/j.nmd.2020.06.004

Neuromuscular Disorders

Volume 30, Issue 8, August 2020, Pages 674-679

https://doi.org/10.1016/j.nmd.2020.06.004 Get rights and content

Highlights

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Two Japanese LGMDR25 patients shared a novel nonsense variant of BVES.
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One patient experienced muscle symptom from childhood.
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One patient showed initial distal muscle weakness.

Abstract

We report two Japanese patients with autosomal recessive limb-girdle muscular dystrophy type R25 (LGMDR25), harboring a novel recurrent homozygous nonsense variant of BVES. Muscle symptoms manifested from childhood to adulthood, initiated in the proximal or distal muscles of the lower limbs, and displayed asymmetric muscle involvement. Similar to the patients in previous reports, these patients also lost ambulation in late middle age. The posterior compartment of the lower limb muscles (biceps femoris, adductor magnus, gastrocnemius, and soleus) was preferentially affected as was the paraspinal muscle. Muscles in the anterior compartment of the thigh were affected in more advanced stages. Both patients had symptomatic atrioventricular block. The POPDC1 protein was undetectable in the muscles of the patients. As observed by transmission electron microscopy, one of the patient samples had fewer caveolae along the sarcolemma than a control sample.

Introduction

POPDC1, the protein product of the BVES gene, is predominantly expressed in striated muscles, highest in skeletal muscles [1]. BVES variants are associated with limb-girdle muscular dystrophy autosomal recessive 25 (LGMDR25), characterized by slowly progressive muscular dystrophy and stress-induced atrioventricular (AV) block [2,3]. Mutant zebrafish in which BVES has been knocked down display muscle fiber disorganization. They also have lower cyclic adenosine 3’,5’-monophosphate binding ability than wildtype counterparts, resulting in TREK-1 current modulation disturbance [2]. Moreover, POPDC1 is also known as caveolae-associated protein; the cardiomyocytes of BVES-null mutant mice exhibit impaired calcium ion profiles, decreased ischemia tolerance, and fewer caveolae than wildtype cardiomyocytes [4]. To date, seven LGMDR25 patients from four unrelated families from Albanian, North Africa, and Belgium have been reported; each family had a different variant: a missense, start-loss, stop-gain, or splicing site variant [2,3]. Here, we present two Japanese patients with a novel recurrent homozygous nonsense BVES variant.

Section snippets

Case reports

Patient 1 is a 67-year-old Japanese man, born to consanguineous parents, with a history of exercise-induced myalgia in the thigh and calf muscles since childhood. His neck and wrist flexion ranges of motion had also been mildly limited since childhood. At 40 years of age, he presented with AV block and dilated cardiomyopathy, and had a pacemaker implanted. At 45 years of age, he displayed gait disturbance and lordosis. Upper limbs weakness was noticed at 57 years of age. Although his symptoms

Discussion

We identified two patients with LGMDR25 (alternatively called LGMD2X). LGMDR25 is characterized by slowly progressive adult-onset muscular dystrophy accompanied by the cardiac conduction abnormality AV block. Seven cases from four unrelated families with variable skeletal muscle phenotypes have been described; four of the seven patients had skeletal muscle involvement and only two of the seven experienced apparent muscle weakness [2,3]. In this section, we focus on the skeletal muscle

Acknowledgements

We thank Megumu Ogawa and Hisayoshi Nakamura for their help. We also thank the patients and their family members for making this work possible.

Funding

This study was supported partly by Intramural Research Grants for Neurological and Psychiatric Disorders of NCNP [grant numbers 2-5, 2-6, 29-4 and 30-9]; AMED [grant numbers JP20ek0109490h0001 and JP20ek0109348s0503]; and Joint Usage and Joint Research Programs, the Institute of Advanced Medical Sciences, Tokushima University [2019, A9 to AI]. The funding sources had no role in the study design, data collection, data analysis, report writing, and submission decision.

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A homozygous loss of function variant in POPDC3: From invalidating exercise intolerance to a limb-girdle muscular dystrophy phenotype
2023, Neuromuscular Disorders
Recessive pathogenic variants in POPDC3 have recently been associated with the rare limb-girdle muscular dystrophy (LGMD) subtype LGMDR26. We studied three siblings and a distantly related individual with a skeletal muscle disorder, harboring the c.486–6T>A splice site variant in POPDC3 in homozygosity. Immunohistochemistry, western blot, and mRNA experiments on patients’ skeletal muscle tissue as well as on patients’ myoblasts were performed to study the pathogenicity of the predicted loss of function mechanism of the variant. Patients mainly presented with invalidating myalgia and exercise intolerance and limited to no segmentary muscle weakness. CK levels were markedly elevated in all patients. A loss of function mechanism at the RNA level was shown (r.485_486insauag, p.Ile163*). Muscle biopsies performed in three out of four patients showed non-specific myopathic features with a marked type 2 fiber predominance and the presence of a large number of severely atrophic fibers with pyknotic nuclear clumps. We show that skeletal muscle symptoms in LGMDR26 may range from an overt late juvenile to young adult-onset limb-girdle muscular dystrophy phenotype to severe exercise intolerance and myalgia, with consistently highly elevated CK levels. We further prove a clear LOF mechanism of POPDC3 in this rare disorder.
Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25
2023, Molecular Therapy
Limb-girdle muscular dystrophy type R25 (LGMDR25) is caused by recessive mutations in BVES encoding a cAMP-binding protein, characterized by progressive muscular dystrophy with deteriorating muscle function and impaired cardiac conduction in patients. There is currently no therapeutic treatment for LGMDR25 patients. Here we report the efficacy and safety of recombinant adeno-associated virus 9 (AAV9)-mediated systemic delivery of human BVES driven by a muscle-specific promoter MHCK7 (AAV9.BVES) in BVES-knockout (BVES-KO) mice. AAV9.BVES efficiently transduced the cardiac and skeletal muscle tissues when intraperitoneally injected into neonatal BVES-KO mice. AAV9.BVES dramatically improved body weight gain, muscle mass, muscle strength, and exercise performance in BVES-KO mice regardless of sex. AAV9.BVES also significantly ameliorated the histopathological features of muscular dystrophy. The heart rate reduction was also normalized in BVES-KO mice under exercise-induced stress following systemic AAV9.BVES delivery. Moreover, intravenous AAV9.BVES administration into adult BVES-KO mice after the disease onset also resulted in substantial improvement in body weight, muscle mass, muscle contractility, and stress-induced heart rhythm abnormality. No obvious toxicity was detected. Taken together, these results provide the proof-of-concept evidence to support the AAV9.BVES gene therapy for LGMDR25.
Early respiratory muscle involvement in LGMDR25: a case report
2022, Neuromuscular Disorders
Citation Excerpt :
The involvement pattern at thigh level is highly consistent. The long head of biceps femoris and adductor magnus are preferentially affected [5,6], followed by vastus medialis, vastus lateralis, vastus intermedius, and semitendinosus [4,6]. With progression, fatty replacement could be found in the short head of biceps femoris, semimembranosus, sartorius, and gracilis muscles.
Limb girdle muscular dystrophy type R25 (LGMDR25) is a rare genetic disorder due to loss-of-function mutations in BVES, characterized by progressive proximal lower limb weakness and atrioventricular block. Here we report a young Chinese man with LGMDR25 who presented with asymmetrical lower limb weakness, myalgia, palpitations and dyspnea on exertion. Muscle imaging demonstrated fatty infiltration of the long head of biceps femoris, adductor magnus, gastrocnemius and soleus, and myoedema of semitendinosus and quadriceps, sparing rectus femoris. ECG showed only mild sinus tachycardia but pulmonary function test suggested prominent respiratory muscle weakness. Our report expands the phenotypical spectrum and indicates the importance of monitoring respiratory function in LGMDR25 patients.
Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1)
2022, Molecular Genetics and Metabolism
Citation Excerpt :
Two of them had an AV block [6]. Indrawati and colleagues described two Japanese patients with the pathogenic BVES variant c.788C>A, p.S263X and onset of muscle weakness at age 44 and 45 years, respectively [8]. Recently, Beecher and colleagues reported a juvenile patient from India with a c.427A>T, p.R143X variant in BVES presenting with muscle weaknes [7].
Popeye domain containing protein 1 (POPDC1) is a highly conserved transmembrane protein essential for striated muscle function and homeostasis. Pathogenic variants in the gene encoding POPDC1 (BVES, Blood vessel epicardial substance) are causative for limb-girdle muscular dystrophy (LGMDR25), associated with cardiac arrhythmia.
We report on four affected children (age 7–19 years) from two consanguineous families with two novel pathogenic variants in BVES c.457C>T(p.Q153X) and c.578T>G (p.I193S). Detailed analyses were performed on muscle biopsies from an affected patient of each family including immunofluorescence, electron microscopy and proteomic profiling.
Cardiac abnormalities were present in all patients and serum creatine kinase (CK) values were variably elevated despite lack of overt muscle weakness. Detailed histological analysis of skeletal muscle, however indicated a myopathy with reduced sarcolemmal expression of POPDC1 accompanied by altered sarcolemmal and sarcoplasmatic dysferlin and Xin/XIRP1 abundance. At the electron microscopic level, the muscle fiber membrane was focally disrupted. The proteomic signature showed statistically significant dysregulation of 191 proteins of which 173 were increased and 18 were decreased. Gene ontology-term analysis of affected biological processes revealed - among others - perturbation of muscle fibril assembly, myofilament sliding, and contraction as well as transition between fast and slow fibers.
In conclusion, these findings demonstrate that the phenotype of LGMDR25 is highly variable and also includes younger children with conduction abnormalities, no apparent muscular problems, and only mildly elevated CK values. Biochemical studies suggest that BVES mutations causing loss of functional POPDC1 can impede striated muscle function by several mechanisms.
Phosphodiesterase type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins
2022, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
Loss-of-function mutations of Popdc1 and Popdc2 in mice and zebrafish established an important role for these genes in cardiac pacemaking and conduction [13,16,17]. Mutations in POPDC1, POPDC2 and POPDC3 have been recently identified in patients suffering from cardiac arrhythmia and/or limb-girdle muscular dystrophy, respectively [17–20]. Moreover, POPDC proteins have also been implicated in atrial fibrillation, long QT syndrome and heart failure [21–23].
Cyclic AMP is a ubiquitous second messenger used to transduce intracellular signals from a variety of Gs-coupled receptors. Compartmentalisation of protein intermediates within the cAMP signaling pathway underpins receptor-specific responses. The cAMP effector proteins protein-kinase A and EPAC are found in complexes that also contain phosphodiesterases whose presence ensures a coordinated cellular response to receptor activation events. Popeye domain containing (POPDC) proteins are the most recent class of cAMP effectors to be identified and have crucial roles in cardiac pacemaking and conduction. We report the first observation that POPDC proteins exist in complexes with members of the PDE4 family in cardiac myocytes. We show that POPDC1 preferentially binds the PDE4A sub-family via a specificity motif in the PDE4 UCR1 region and that PDE4s bind to the Popeye domain of POPDC1 in a region known to be susceptible to a mutation that causes human disease. Using a cell-permeable disruptor peptide that displaces the POPDC1-PDE4 complex we show that PDE4 activity localized to POPDC1 modulates cycle length of spontaneous Ca²⁺ transients firing in intact mouse sinoatrial nodes.
Severe adolescent-onset limb-girdle muscular dystrophy due to a novel homozygous nonsense BVES variant
2021, Journal of the Neurological Sciences

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Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES

Highlights

Abstract

Introduction

Section snippets

Case reports

Discussion

Acknowledgements

Funding

Dev Biol

Genet Med

J Neurol Sci

Neuromuscul Disord

POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking

J Clin Invest