A missense c.80G＞A mutation in the CAV3 gene in a Han Chinese family with rippling muscle disease

doi:10.21203/rs.3.rs-4085678/v1

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Research Article

A missense c.80G＞A mutation in the CAV3 gene in a Han Chinese family with rippling muscle disease

https://doi.org/10.21203/rs.3.rs-4085678/v1

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Background

Rippling muscle disease (RMD), one of the special clinical phenotypes of caveolinopathies, is characterized by muscle hyperexcitability causing by mutations in the CAV3 gene. Few data exist on muscle MRI in patients with RMD, frequently reported as normal.

Methods

Here, we describe a Han Chinese family with RMD. Whole exome sequencing (WES), muscle MRI, and tissue biopsy were performed in this study.

Results

The proband and his mother presented with RMD, which was initially noticed during their childhood or adolescence, accompanied with increased level of serum creatine kinase (CK). Biopsy specimen illustrated slight variation in fiber size and increased numbers of internal nuclei in the muscle fibers, without obvious atrophy. Muscle MRI of the thighs showed short-tau inversion recovery (STIR) hyperintensity without fatty replacement. WES identified a heterozygous missense mutation of c.80G>A (p.R27Q) in the CAV3 gene.

Conclusions

Our findings deepen our awareness of the muscle MRI and pathological features of hereditary RMD. Regarding muscle MRI, this study first reports STIR hyperintensity in the thighs, which may be linked with muscle oedema.

Rippling muscle disease

Whole exome sequencing

caveolin-3

CA3 gene

Caveolae, also called litter caves, are characterized by bulb-shaped invaginations that are one of the most important features of the plasma membrane in many mammalian cells, such as endothelial cells, adipocytes, and muscle cells [1]. The core components for the formation of caveolae are caveolin-1 (CAV1), caveolin-3 (CAV3), cavin1/PTRF. Besides, other members, including caveolin-2 (CAV2), cavin2, cavin3, and cavin4, also play important role in the formation and stability of caveolae [2]. CAV1 is expressed in the vast majority of cell types, especially adipocytes, endothelial and epithelial cells, fibroblasts, and smooth-muscle cells. CAV2 is tightly co-expressed with CAV1 in a wide range of cells, whereas CAV3 is specifically expressed in muscle cells [3, 4]. Three genes encode members of caveolin family in mammals. In humans, both CAV1 and CAV2 are located on chromosome 7 q31.1, while CAV3 is found on a different chromosome (3p25) [4, 5]. Mutations in the CAV3 gene lead to various muscle disorders with partial overlap, including limb-girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease (RMD), distal myopathy, benign hyperCKemia, and familial hyertrophic cardiomyopathy [6]. RMD, mainly inherited as autosomal dominant trait, is a rare muscle disorder featured by increased muscle irritability. Clinical signs encompass mechanical stimuli-induced muscle mounding, rapid contraction, and rolling movements across muscle groups (“rippling”) [7]. Up to now, more than 70 pathogenic mutations in the CAV3 gene have been identified (https://www.ncbi.nlm.nih.gov/clinvar). In this study, we report a heterozygous missense mutation of c.80G>A (p.R27Q) in the CAV3 gene in a Han Chinese family with hereditary RMD, presenting an autosomal dominant inheritance. Previously, such missense mutation has also been described in patients with distal myopathy [8, 9]. However, the correlation between genotype and phenotype remains unclear. In addition, we also pay attention to the histological, electrophysiological, and muscle imaging findings of patient with hereditary RMD caused by mutation in the CAV3 gene.

Subjects and clinical assessment

Our research was approved by the Ethics Committee of Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College. All individuals participated in the study offered informed written consent. A Han Chinese family with three generations including 15 members was analyzed in this study. Medical history collecting and standard neurological examinations were conducted by two of our experienced neurologists (YS and GH). A comprehensive genealogical investigation originated from information provided by the proband. In addition, laboratory tests, electromyography examination, and muscle magnetic resonance imaging (MRI) were also performed for the proband. Axial T1-weighted spin echo and short-tau inversion recovery (STIR) sequences on a 3.0-tesla Philips MR scanner were utilized to evaluate fatty degeneration and edema/inflammation change, respectively. An open muscle biopsy was done under local anesthesia after receiving the proband’s consent. Muscle samples were frozen immediately in liquid nitrogen pre-cooled isopentane. Cryostat sections were cut from transversely oriented muscle blocks in order to carry out routine stains, containing hematoxylin and eosin (H&E), modified Gomori trichrome (MGT), periodic acid-Schiff (PAS), oil red O (ORO), and nicotinamide adenine dinucleotide (NADH) staining.

Molecular genetic analysis

With written informed consent, 4 ml peripheral blood samples were collected from the proband (III-4) and three other family members (II-3, II-4, and III3) respectively. Total genomic DNA was extracted from peripheral leukocytes using standard techniques [10]. In this study, the whole-exome sequencing (WES) was carried out in order to identified the disease-related mutation of this family. Genomic DNA was randomly sheared into different fragments with length ranging from 150 to 250 bp. Those fragments were subsequently processed by three major procedures: end-repairing, A-tailing, adapter ligation and polymerase chain reaction (PCR) amplification. Thereafter, they were further modified, amplified, purified, and hybridized to the exome array for enrichment. DNA libraries were sequenced by the Illumina Novaseq system (Illumina, San Diego, CA, USA) with paired-end 150-bp reads. The raw data were aligned against the human reference genome (hg 19) with the Burrows Wheeler Aligner (BWA) (http://bio-bwa.sourceforge.net/). Duplicate reads were discarded with Picard software (http://broadinstitute.github.io/picard/). Genome Analysis ToolKit (GAKT) and SNPs annotation variation ANNOVAR software were used for identifying the single-nucleotide polymorphisms (SNPs) and annotating candidate variants, respectively. We filtered and selected the variants according to the minor allele frequency with a cut-off value of < 0.05 in four databases (1000 Genome Project, HapMap, dbSNP and in‐house Chinese local database). The pathogenicity of the potential variants was predicted by using online tools, such as PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2), SIFT (http://sift.jcvi.org), Mutation Taster (http://www.mutationtaster.org), and CADD (http://cadd.gs.washington.edu). The genes of irrelevant inherited modes and synonymous variants were excluded. Interpretations of the variants were according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines [11]. The standard Sanger sequencer (BigDye® Terminator v3.1, Applied Biosystems, Foster City, CA, USA) was employed to confirm the identified potential disease-associated variant.

Clinical investigations

The pedigree of the family was illustrated in Fig. 1. Patient 1 (the proband, III-4), a 14-year-old Han Chinese man with normal spontaneous vaginal delivery and development, was admitted to our hospital due to postexercise muscle stiffness in his lower limbs for 8 years. He complained of difficulty in relaxing the muscles and painful cramps after strenuous exercise or exposure to cold temperature. Although he presented with easy fatigability and decreased stamina, there was no obvious muscle weakness in his four limbs. Respiratory or cardiac symptoms were absent in the proband. On admission, his vital signs were stable with the temperature of 36.5 ℃, the heart rate of 78 beats per minute, the respiratory rate of 18 breaths per minute, and the blood pressure of 102/78 mmHg. Neurological examination revealed normal muscle strength and preserved tendon reflexes in his four limbs without focal wasting. It’s worth noting that rolling muscle movements and localized muscle mounding were noted in his legs, chest, and back after percussion (Video S1). There was no change in bladder and bowel habits and no sensory loss. Laboratory tests showed increased serum creatine kinase (CK) (3912 IU/L, reference range 0-200 IU/L), lactate dehydrogenase (479 IU/L, reference range 120–250 IU/L), creatine kinase isoenzyme (120 IU/L, reference range 0–25 IU/L), alanine transaminase (124 IU/L, reference range 9–50 IU/L), and aspartate aminotransferase (253 IU/L, reference range 15–40 IU/L). Other examinations including complete blood picture, liver and renal function, clotting profile, C-reactive protein, erythrocyte sedimentation rate, thyroid hormones, and tumor markers were all within normal limits. Investigations of 24-hour ambulatory electrocardiographic monitoring and transsternal echocardiography showed normal findings. Needle electromyography (EMG) suggested patchy myopathic changes in his proximal leg muscles, including an abnormal motor unit action potential with low amplitude and increased percentage of polyphase waves as well as an early recruitment phenomenon, without myotonic discharge. Besides, during transient muscle mounding induced by muscle percussion, EMG revealed distinct electrical silence.

Patient 2 (the proband’s mother, II-3), a previously healthy 47-year-old housewife, was called back to our hospital. She had painful cramps in her lower limbs after strenuous exercise for 30 years. The symptoms improved after rest spontaneously. She also noticed involuntary muscle wriggle in her legs while the muscles in these areas were extended or flexed strongly. On neurological examination, muscle strength, sensory perception, and tendon reflexes were normal in her four limbs, and tests of functions of the cognition, cranial nerves, and cerebellum were also unremarkable. However, transient forceful contraction, painful local mounding, and rolling muscle movements could easily be induced by suddenly mechanical stimuli, such as tapping, stretching, or squeezing of the leg muscles. Serological examination yielded an increased CK (2100 IU/L, reference range 0-200 IU/L), but the other tests were otherwise normal. The result of Needle EMG was patchy myopathic changes, with no myotonic potentials or myokymic discharges.

Muscle MRI and pathology

Muscle MRI of the thighs of the proband, performed in the absence of foregoing exercise or trauma, demonstrated symmetric and patchy hyperintensities in bilateral semimembranosus, semitendinosus, biceps femoris long head, and sartorius muscles on STIR imaging (Fig. 2A). Whereas, abnormal signal changes were not found in above-mentioned muscles on T1-weighted spin echo, indicating no fatty infiltration (Fig. 2B). There was no significant atrophy of both thighs. Furthermore, muscle imaging of the upper limbs was also performed for patient 1, but the arms did not show any abnormalities.

Biopsy specimen of the left-sided rectus femoris was conducted in the proband. H&E stain illustrated mild variation in fiber size and some fibers with nuclear migration, without perifascicular atrophy, perimysial and endomysial lymphocytic inflammation, rimmed vacuoles, or increased endomysial connective tissue (Fig. 3A). Ragged-red fibers were absent on GMT stain (Fig. 3B).

Identification of the mutation in the CA3 gene

In order to seek out potentially causative genetic evidence, based on the obvious hereditary history of this family, the genetic testing was performed for the proband (II-8) and his three family members (II-3, II-4 and III-3) after obtaining written informed consent. A heterozygous missense mutation, c.80G>A (NM_033337), in the exon 1 of the CAV3 gene was identified in the proband by WES (Fig. 4). Such mutation converts amino acid 27 from arginine to glutamine (p.R27Q). Moreover, the same genetic mutation was also detected in the proband’s mother who had identical clinical presentation of RMD. The pathogenicity of this variant is classified as a pathogenic mutation according to the ACMG guideline [11]. It was a pity that we failed to obtain the blood sample of family members of the first generation.

RMD, one of the special clinical phenotypes of caveolinopathies, was first described in a family with an involuntarily rolling contraction of the muscles induced by mechanical stimuli in 1975, and the first pathogenic variant in the CAV3 gene was identified in five families with autosomal-dominant RMD until 2001 [12, 13]. Thereafter, an increasing number of pathogenic mutations in the CAV3 gene have been found out. In this study, we reported a heterozygous missense mutation of c.80G>A (p.R27Q) in exon 1 of the CAV3 gene in a Han Chinese family with RMD. Previously, such variation has also been documented in patients with distal myopathy, LGMD1C, benign hyperCKemia, and overlapping muscle disease phenotypes [9, 14–16]. Although R27Q mutation is not unusual, it has been rarely reported in Chinese family with RMD.

To our knowledge, RMD is featured by signs of muscle hyperexcitability, including percussion-induced rapid contraction, muscle mounding, and electrically silent muscle contractions (rippling muscle), resulting in muscle stiffness, pain, and cramps. Apart from hyperexcitable symptoms of skeletal muscle, moderate hyperCKemia, mild muscle atrophy, and distal muscle weakness are also frequent in patients with RMD [6, 9, 17, 18]. Moreover, some infrequent symptoms, such as toe walking, easy fatigability, and proximal weakness, have also been noted in RMD [19, 20]. RMD therefore overlaps with other clinical phenotypes, and there is no significant correlation between genotype and phenotype of caveolinopathies [21, 22]. The same pathogenic variant can give rise to heterogeneous clinical phenotypes and histopathologic changes, even in individuals within the same family. In this study, the proband and his mother presented with RMD, which was initially noticed during their childhood or adolescence, accompanied with increased level of serum CK. Muscle weakness and atrophy of four limbs remain absent in those two patients so far. Based on the WES and co-segregated analysis, a pathogenic c.80G>A mutation in the CAV3 gene was identified in this family, showing an autosomal dominant inheritance. The clinical presentations can be classified as isolated RMD, without overlapping syndrome. After carefully checking the first generation’s medical information, we were not difficult to notice that the proband’s grandfather had increased serum CK. In spite of failing to obtain blood samples from the first generation for further genetic analysis, we speculate that the proband’s grandfather may carry the same pathogenic variant in CAV3 gene, resulting in asymptomatic hyperCKemia instead of RMD. This observed intrafamilial phenotypic variability suggests that other genetic modifiers may exist.

CAV3 consists of 151 amino acids and contains three separate domains. The N’- and C’-terminal portions are exposed to the cytoplasm and the middle hydrophobic portion is inserted into the lipid bilayer in the form of a hairpin loop [7, 23]. The caveolin scaffolding domain, located at the juxta membrane part of the N’-terminal cytoplasmic tail, is associated with many signaling pathways and aggregates caveolins into larger assemblies. Nine CAV3 monomers assemble to make up a toroidal shape complex, leading to membrane invagination into pits, the so-called caveolae [24]. CAV3 has been shown to play crucial roles in muscle development and repair, energy metabolism, lipid metabolism, T tubule system, regulation of potassium channel and adrenergic receptors, and mitochondrial homeostasis [7]. Arg27 is located at the highly conserved amino acid sequences of N’-terminal portion. Previous studies have confirmed that c.80G>A (p.R27Q) mutation in the CAV3 gene, also previously reported as R26Q, leaded to dysfunction of caveolins. First and foremost, CAV3 R27Q mutation increases the Triton solubility and oligomeric state of CAV3 and decreases the steady-state expression levels of CAV3, resulting in intracellular retention of CAV3 in Golgi compartment and reduced expression of CAV3 at the surface of the sarcolemma [25]. In the absence of CAV3, dysferlin is rapidly endocytosed and membrane repair is compromised [26]. Furthermore, such mutation is linked with deregulations in distinct signaling pathways. CAV3 R27Q myotubes are unable to assemble sufficient amounts of functional caveolae at the sarcolemma, contributing to uncoupling the regulation of IL6/STAT3 signaling with mechanical stress [27]. Surface biotinylation experiments show that CAV3 R27Q mutation decreases epidermal growth factor signaling and the internalization of TrkA [28]. Those signaling pathways are important for the development and maintenance of the neuromuscular junction as well as muscle development and regeneration [29, 30].

Regarding the muscle pathology of caveolinopathy, routine stains usually reveal abnormal findings with nonspecific changes, such as disseminated atrophic fibers, some fibers with internal nuclei, foci of degeneration with necrosis and phagocytosis, proliferation of endomysial and perimysial connective tissue, and variation in fiber size [31, 32]. Furthermore, typical dystrophic changes with numerous endomysial inflammatory infiltration in the muscle fibers have been rarely described [32, 33]. Although most immunohistochemical studies demonstrated reduced immunoreaction of CAV3, a quarter of patients had normal expression of CAV3 along the surface of sarcolemma that may increase the probability of misdiagnosis for clinician [34]. In our study, we just found slight variation in fiber size and increased numbers of internal nuclei in the muscle fibers, without obvious atrophy. Hence, it is sometimes difficult to distinguish caveolinopathy from other myopathies by pathology alone.

Previously, the majority of patients with RMD demonstrated normal skeletal muscle imaging. Nevertheless, abnormal skeletal MRI features have been rarely described in patients with caveolinopthies [22, 35, 36]. In previous reports of patients with RMD, peripheral rectus femoris and semitendinosus muscles are commonest affected, presenting significant fatty infiltration with a symmetrical distribution on T1-weighted spin echo [22, 34]. Peripheral rectus femoris involvement in a ring-shaped pattern appears to be specific for this disorder. In addition, some patients had more extensive high T1W signal intensities, involving in the semimembranosus, biceps femoris, gracilis, adductor longus, and gastrocnemius muscles [22]. It is worth noting that the muscle MRI of the proband did not reveal fatty replacement or atrophy. However, axial STIR sequences disclosed symmetric and patchy hyperintensities in bilateral semimembranosus, semitendinosus, biceps femoris long head, and sartorius muscles. After retrospectively scanned the muscle biopsy, we could not find any inflammatory infiltration or necrosis. We therefore speculate that these STIR hyperintensities might be linked with muscle oedema. As far as we know, STIR hyperintensity on muscle MRI has been previously described in only one patient with asymptomatic hyperCKemia caused by the CAV3 gene mutation [37].

Several limitations need to be emphasized in our study. Firstly, we fail to obtain the informed consent of the proband’s mother for conducting muscle MRI and biopsy examinations. Whether there are heterogeneous muscle MRI findings and histopathologic changes between individuals within this family are unknown. Secondly, absent genetic testing of the first generation has an influence on exploring the relationship between genotype and phenotype. Finally, long-term clinical and radiological follow-up for our patients has not been included in this study. To better evaluate the progression of muscle symptoms and the changes of abnormal signal intensity on muscle MRI, a multicenter study with larger sample sizes should be further performed.

In conclusion, we identified a heterozygous missense mutation of c.80G>A (p.R27Q) in the CAV3 gene in a Han Chinese family, which is associated with hereditary RMD. RMD can overlap with other clinical phenotypes. Early recognition of special clinical phenotypes plays important role in timely diagnosis of caveolinopathies. Regarding muscle MRI features of RMD, this study first reports STIR hyperintensity in the thighs, which may be linked with muscle oedema.

Funding There was no specific funding for this study

Compliance with ethical standards

Conflict of interest We as authors declare that there are no conflicts of interest.

Ethical standards All procedures were approved by the Ethics committee of Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, and carried out in accordance with the principles of Helsinki Declaration.

Informed consent Informed consent was obtained from all individual participants included in the study.

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A missense c.80G＞A mutation in the CAV3 gene in a Han Chinese family with rippling muscle disease

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Abstract

Background

Methods

Results

Conclusions

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Introduction

Materials and methods

Subjects and clinical assessment

Molecular genetic analysis

Results

Clinical investigations

Muscle MRI and pathology

Discussion

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References

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