Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: TPM3
SNOMEDCT: 240084007;
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38) : 1:154,155,308-154,192,100 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Congenital myopathy 4A, autosomal dominant | 255310 | Autosomal dominant | 3 |
| Congenital myopathy 4B, autosomal recessive | 609284 | Autosomal recessive | 3 |
Tropomyosins are proteins that were first isolated from skeletal muscle, but later identified in many nonmuscle tissues. Vertebrates have at least 4 different tropomyosin genes: TPM1 (191010), TPM2 (190990), TPM3, and TPM4 (600317). Both muscle and nonmuscle forms of the protein are expressed by alternative splicing of each of the 4 genes (MacLeod et al., 1985; Laing et al., 1995).
MacLeod et al. (1985) isolated a cDNA corresponding to tropomyosin from a human fibroblast cDNA library. A 1.1-kb mRNA transcript encoded a 284-amino acid protein with similarity to chicken smooth muscle tropomyosin. A 2.5-kb mRNA transcript encoded a 247-amino acid cytoskeletal tropomyosin protein. The findings indicated that nonmuscle cells express both muscle and non-muscle types of tropomyosin. MacLeod et al. (1985) suggested that both cytoskeletal tropomyosin and skeletal muscle tropomyosin are derived from a common structural gene by alternative splicing.
MacLeod et al. (1986) and Clayton et al. (1988) isolated cDNAs corresponding to human tropomyosin-3. In non-muscle tissues, the gene produces a 2.5-kb mRNA encoding a 248-amino acid cytoskeletal protein with a molecular mass of approximately 30 kD. In muscle, alternative splicing of the gene produces a 1.3-kb mRNA encoding a 285-amino acid protein.
TPM3/NTRK1 Fusion Gene
Martin-Zanca et al. (1986) identified a biologically active cDNA of a transforming gene in a human colon carcinoma cell line. The gene, referred to as TRK protooncogene, is a chimera containing sequences of both tropomyosin-3 and a tyrosine kinase. The TRK protooncogene was predicted to encode a 641-amino acid transmembrane tyrosine kinase expressed in neural tissues. The protein was identified by its ability to transform rodent cells in gene transfer assays. Martin-Zanca et al. (1986) suggested that the chimeric gene was likely formed by a somatic rearrangement between the 2 genes, resulting in the replacement of the extracellular domain of the transmembrane receptor with the first 221 amino acids of the tropomyosin-3 molecule.
Mitra et al. (1987) expressed the entire coding sequence of the TRK oncogene in E. coli. Antisera raised against these bacteria-synthesized TRK polypeptides were used to identify the gene product of the TRK oncogene as a 70-kD protein.
Clayton et al. (1988) determined that the TPM3 gene spans 42 kb and contains 13 exons; only 5 exons are common to both the 2.5- and 1.3-kb mRNA transcripts. A comparison of the structure of exons encoding the amino-terminal sequences of the muscle and non-muscle isoforms suggested that the TPM3 gene evolved by a specific pattern of exon duplication with alternative splicing.
By in situ hybridization and studies of somatic cell hybrids, Martin-Zanca et al. (1986) mapped the TPM3 gene to chromosome 1q31-q41.
Radice et al. (1991) assigned the TPM3 gene to 1q by Southern blot analysis of a panel of human-rodent somatic cell hybrids. Using the same probe, they localized the gene to 1q31 by in situ hybridization to human metaphase chromosomes. Wilton et al. (1995) reassigned the TPM3 gene to 1q22-q23 by fluorescence in situ hybridization.
Linkage findings in a family with nemaline myopathy caused by mutation in the TPM3 gene (CMYO4A; see 255310) by Laing et al. (1995) placed TPM3 in close proximity to NTRK1 (191315), which had been reassigned to 1q23-q24 (Morris et al., 1991), so that a gene fusion rearrangement involving these 2 genes would not be cytologically detectable.
Using a human cDNA fragment of the TPM3 gene and a mapping panel from a murine interspecific cross, Gariboldi et al. (1995) mapped the mouse Tpm3 gene to chromosome 3.
TPM3/NTRK1 Fusion Gene
By a combination of study of somatic cell hybrids and in situ hybridization, Miozzo et al. (1990) mapped the TPM3/NTRK1 (TRK) fusion gene to 1q32-q41. Morris et al. (1991) localized the TRK gene to a more proximal location, 1q23-q24, by in situ hybridization.
In skeletal muscle, tropomyosin isoforms are components of the thin filaments of the sarcomere and mediate the effect of calcium on the actin-myosin interaction. TPM3 is expressed mostly in slow, type 1 muscle fibers. Two muscle-specific isoforms of tropomyosin, an alpha and a beta, form an alpha-helical dimer, bind head to tail, and lie in the major groove of filamentous actin with each tropomyosin molecule binding to 7 actin molecules (Laing et al., 1995).
Tropomyosin, together with actin (ACTA1; 102610) and troponin (see, e.g., TNNT1, 191041), constitutes the basic thin filament structural and calcium-regulatory machinery that interacts with myosin when muscle contracts. Tropomyosin polymerizes head-to-tail with other tropomyosin molecules into long strands spanning the whole thin filament length, and binds to different actin monomers. The key function of tropomyosin is in cooperatively switching the location of the actin tropomyosin interface between active and relaxed states under the control of troponin, calcium, and myosin heads. Marston et al. (2013) noted that the actin-binding interface motifs in tropomyosin are repeated motifs common to all tropomyosin molecules, and include K6-K7, K48-K49, R90-R91, and R167-K168, which interact with D25 in actin, and 3 additional tropomyosin motifs, E139, E181, and E218, which interact with a cluster of actin motifs at K326, K328, and R147.
Role in TRK Protooncogene
Coulier et al. (1989) found that the 221 amino-terminal residues of the TPM3 protein are substituted for the external domain of a putative tyrosine-kinase cell surface receptor to create the TRK oncogene. Since the 2 components giving rise to the TRK oncogene are close together on chromosome 1, no microscopically discernible chromosome abnormality was found.
By transfection assay, Bongarzone et al. (1989) found that TRK was activated in tumor cells, both primary tumor and/or metastasis, in 4 of 16 patients with papillary thyroid carcinoma.
Hempstead et al. (1991) and Kaplan et al. (1991) identified the TRK gene product as a nerve growth factor receptor.
Loeb et al. (1991) presented results indicating that TRK was necessary for functional nerve growth factor signal transduction. Cordon-Cardo et al. (1991) presented evidence that the product of the TRK protooncogene was sufficient to mediate signal transduction processes induced by nerve growth factor and neurotrophin-3 (162660). Ehrhard et al. (1993) reported that TRK is expressed in monocytes; this finding as well as others suggested that nerve growth factor is an immunoregulatory cytokine acting on monocytes in addition to its neurotrophic function.
The TPM3 gene is involved with the neighboring gene for neurotrophic tyrosine kinase receptor type 1 (NTRK1; 191315) in a somatic rearrangement that creates the chimeric TRK oncogene. In 3 of 8 papillary thyroid carcinomas, Butti et al. (1995) found that replacement of the extracellular domain of the NTRK1 gene by sequences coding for the 221 N-terminal residues of the TPM3 gene was responsible for the oncogenic NTRK1 activation. In all 3 tumors, the illegitimate recombination involved the 611-bp NTRK1 intron placed upstream of the transmembrane domain and the TPM3 intron located between exons 7 and 8. Therefore, due to the displacing mechanism, all of the TPM3/NTRK1 gene fusions encoded an invariable transcript and the same chimeric protein of 70 kD, which was constitutively phosphorylated on tyrosine. In 2 of the 3 tumors, the simultaneous presence of the reciprocal products of the TPM3/NTRK1 recombination (5-prime-TPM3/3-prime NTRK1 and 5-prime NTRK1/3-prime TPM3) and the previously demonstrated localization of both genes on 1q led Butti et al. (1995) to suggest that an intrachromosomal inversion was responsible for their recombination. To understand the molecular basis predisposing NTRK1 and TPM3 to being a recurrent target of illegitimate recombination, they determined the nucleotide sequence around the breakpoints of the recombination products in all 3 patients and in the corresponding regions from the normal genes. In these regions, they found some recombinogenic elements as well as palindromes, direct and inverted repeats, and Alu family sequences.
Autosomal Dominant Congenital Myopathy 4A
In affected members of a large family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Laing et al. (1995) identified a heterozygous mutation in the TPM3 gene (M9R; 191030.0001) that segregated with the disorder.
In affected members of a French family with autosomal dominant CMYO4A, Penisson-Besnier et al. (2007) identified a heterozygous mutation in the TPM3 gene (R168H; 191030.0005).
Clarke et al. (2008) identified 5 different heterozygous TPM3 mutations (see, e.g., 191030.0005; 191030.0007; 191030.0008), in affected members of 6 unrelated families with CMYO4A and congenital fiber-type disproportion (CFTD) on skeletal muscle biopsy. The mutations were identified among 23 unrelated probands with CFTD, making mutations in the TPM3 gene the most common cause of CFTD to date.
In a 38-year-old woman with CMYO4A associated with cap structures on skeletal muscle biopsy who had previously been reported by Fidzianska (2002), Ohlsson et al. (2009) identified a heterozygous mutation in the TPM3 gene (R168C; 191030.0009).
De Paula et al. (2009) reported a 42-year-old man with cap myopathy associated with a heterozygous de novo mutation in the TPM3 gene (R168H; 191030.0005).
Waddell et al. (2010) reported a man with CMYO4A and cap myopathy on skeletal muscle biopsy that was associated with a de novo heterozygous R168C mutation in the TPM3 gene.
Malfatti et al. (2013) reported a man of French Canadian origin with early-onset myopathy and a de novo heterozygous R168C mutation in the TPM3 gene.
In 2 affected members of a family with autosomal dominant CMYO4A, Schreckenbach et al. (2014) identified a heterozygous missense mutation in the TPM3 gene (L149I; 191030.0012).
Marttila et al. (2014) reported 11 unrelated families with CMYO4A due to heterozygous missense mutations in the TPM3 gene. Six novel heterozygous mutations and several recurrent mutations affecting codon 168 (R168C, R168H) were identified.
Xu et al. (2021) reported a 10-year-old Chinese girl with CMYO4A associated with a heterozygous R168G mutation in the TPM3 gene (R168G; 191030.0008) that was inherited from her clinically unaffected father. Her brother, who also carried the mutation, had a milder phenotype. The authors noted the intrafamilial variability.
In a 47-year-old man with CMYO4A, Bevilacqua et al. (2022) identified a heterozygous mutation in the TPM3 gene (E237K; 191030.0013).
Among 25 Brazilian families with a clinical diagnosis of nemaline myopathy, Gurgel-Giannetti et al. (2022) found 1 (4%) who carried a heterozygous missense mutation in the TPM3 gene (R168C). The mutation was present in a father and son (family 7) with congenital myopathy, scoliosis, and nocturnal hypoventilation; both were ambulatory. The findings suggested that mutations in the TPM3 gene are not a common cause of nemaline myopathy.
In 2 unrelated children with CMYO4A characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, Donkervoort et al. (2015) identified 2 different de novo heterozygous in-frame deletions in the TPM3 gene (E218del, 191030.0010 and E224del, 191030.0011). In vitro studies showed that both mutations resulted in increased calcium sensitivity, increased active interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function. The findings conformed to the predictions made by Marston et al. (2013) in in vitro studies. A mutation at one of the tropomyosin binding sites in the actin molecule (K328N; 102610.0016) resulted in a similar phenotype characterized by hypercontractility (Jain et al., 2012).
Autosomal Recessive Congenital Myopathy 4B
In an Iranian patient, born of consanguineous parents, with severe autosomal recessive congenital myopathy-4B (CMYO4B; 609284), resulting in death at 21 months of age, Tan et al. (1999) identified a homozygous nonsense mutation in the TPM3 gene (Q32X; 191030.0004). Each mutation was inherited from an unaffected parent. The authors hypothesized that the patient had no functional TPM3. The patient was identified from a study of 40 unrelated patients diagnosed with congenital myopathy associated with nemaline rods on skeletal muscle biopsy.
In a patient with CMYO4B, Wattanasirichaigoon et al. (2002) identified compound heterozygous mutations in the TPM3 gene (191030.0002 and 191030.0003).
In affected members of 2 Turkish families with CMYO4B, Lehtokari et al. (2008) identified a homozygous mutation in the TPM3 gene (191030.0006). Haplotype analysis suggested a founder effect.
Based on molecular modeling, Marston et al. (2013) predicted that mutations affecting certain TPM3 residues involved in the actin binding sites would result in higher calcium sensitivity, higher filament sliding speeds, and a gain-of-function effect. In contrast, in vitro studies showed that mutations affecting other regions, including R167H (191030.0005), resulted in lower calcium sensitivity, slower sliding speeds, and a hypocontractile phenotype. Marston et al. (2013) suggested that consideration of the effects of the mutations on muscle contractility would be more predictive of the phenotype than histopathology studies.
Corbett et al. (2001) generated a transgenic mouse model expressing an autosomal dominant mutant of TPM3 (M9R; 191030.0001) previously identified in a human patient with nemaline myopathy. Rods were found in all muscles, but to varying extents which did not correlate with the amount of mutant protein present. In addition, a pathologic feature not commonly associated with this disorder, cytoplasmic bodies, was found in the mouse and subsequently identified in human samples. Hypertrophy of fast, type 2B (glycolytic) fibers was apparent at 2 months of age. Muscle weakness was apparent in mice at 5 to 6 months of age, mimicking the late onset observed in humans with this mutation. The onset of weakness correlated with an age-related decrease in fiber diameter and suggested that early onset may be prevented by hypertrophy of fast, glycolytic fibers. The authors suggested that the clinical phenotype may be precipitated by a failure of the hypertrophy to persist and therefore compensate for muscle weakness.
In affected members of a large family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Laing et al. (1995) identified a heterozygous T-to-G transversion in exon 1 of the TPM3 gene, resulting in a met9-to-arg (M9R) substitution in a highly conserved residue located at the N-terminal end of the protein. The region may be important for head-to-tail association of tropomyosin molecules and may be crucial to actin binding. Laing et al. (1995) noted that actin binding was completely inhibited by removal of the N-terminal 9 amino acid residues.
Variant Function
Michele et al. (1999) used adenoviral gene transfer to fully differentiated rat adult myocytes in vitro to determine the effects of nemaline myopathy mutant human tropomyosin expression on striated muscle sarcomeric structure and contractile function. The mutant tropomyosin was expressed and incorporated correctly into sarcomeres of adult muscle cells. The primary defect caused by expression of the mutant tropomyosin was a decrease in the sensitivity of contraction to activating Ca(2+), which could help explain the hypotonia seen in nemaline myopathy. The M9R mutant tropomyosin expression did not directly result in nemaline rod formation, which suggested that rod formation is secondary to contractile dysfunction and that load-dependent processes are likely involved in nemaline rod formation in vivo.
Corbett et al. (2005) found that skeletal muscle from both transgenic mice and human patients with the TPM3 M9R mutation had decreased levels of beta-tropomyosin (TPM2; 190990), and that the timing of increased levels of the mutant TPM3 protein in muscle coincided with a decrease in TPM2 levels. In vertebrates, the preferred pairing of tropomyosin dimers is an alpha/beta heterodimer; however, Western blot analysis of the tropomyosin filament dimers from tissue with the M9R mutant protein showed a decrease in the TPM3/TPM2 heterodimer, with a shift to mutant TPM3 homodimers. The M9R mutation lies within the region of overlap for head-to-tail interactions between dimer pairs. Corbett et al. (2005) suggested that the M9R mutant TPM3 protein changes the composition of sarcomeric thin filaments and the regulation of muscle contraction, resulting in disease manifestations.
In a patient with autosomal recessive congenital myopathy-4B (CMYO4B; 609284), Wattanasirichaigoon et al. (2002) identified compound heterozygous mutations in the TPM3 gene: a c.857A-C transversion (designated 915A-C in the article, based on a GenBank reference sequence) in exon 9sk, resulting in a TER285SER substitution and the addition of 57 amino acids; and a mutation at the acceptor splice site of the same exon, resulting in exon skipping (191030.0003). Based on numbering from the first met codon (Clarke et al. (2008)), this mutation is designated TER286SER (X286S). The patient's asymptomatic father was heterozygous for the X286S mutation, and his asymptomatic mother was heterozygous for the splice site mutation. The patient was identified from a study of 40 unrelated patients with nemaline myopathy.
For discussion of the IVS9-1G-A mutation in the TPM3 gene that was found in compound heterozygous state in a patient with congenital myopathy-4B (CMYO4B; 609284) by Wattanasirichaigoon et al. (2002), see 191030.0002.
In an Iranian patient, born of consanguineous parents, with congenital myopathy-4B (CMYO4B; 609284), Tan et al. (1999) identified a homozygous C-to-T transition in exon 1 of the TPM3 gene, resulting in a GLN31TER substitution. Based on numbering from the first met codon (Clarke et al. (2008)), this mutation is designated GLN32TER (Q32X). Although no neonatal problems were reported, the infant showed extremely delayed motor development and died at age 21 months due to respiratory insufficiency resulting from an infectious illness. Muscle biopsy showed type 1 fiber hypotrophy and atrophy, with a mild predominance of type 2 fibers. Nemaline bodies were present in type 1 fibers only.
In 4 affected members of a French family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Penisson-Besnier et al. (2007) identified a heterozygous c.503G-A transition in exon 5 of the TPM3 gene, resulting in an ARG167HIS substitution. Although most patients had symptoms in childhood, all remained ambulatory as adults. Clarke et al. (2008) noted that based on numbering from the first met codon this mutation is designated ARG168HIS (R168H).
In a father and daughter with congenital myopathy, Clarke et al. (2008) identified the R168H mutation in the TPM3 gene. Both patients had onset of hypotonia in infancy and were able to run in late adolescence. At age 60, the father could walk, had impaired nocturnal ventilation, showed distal more than proximal weakness, and had scoliosis with lumbar lordosis. Skeletal muscle biopsy was consistent with nemaline myopathy. At age 20, the daughter was able to run, had decreased forced vital capacity, mild proximal weakness, and mild scoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD) The findings of both nemaline myopathy and CFTD in patients with the same mutation showed that TPM3 mutations can cause a range of histologic changes, and suggested that there is a close relation between nemaline myopathy and CFTD.
De Paula et al. (2009) reported a 42-year-old man with the R168H mutation who showed cap myopathy on skeletal muscle biopsy. He had hypotonia in the first months of life, delayed motor development, and distal weakness of the lower limbs with frequent falls in childhood. At age 7 years, he had flat feet in valgus, long narrow face, high-arched palate, and mild lumbar hyperlordosis. Tendon reflexes were absent. The clinical course was stable until presentation at age 42 with inability to run, difficulty climbing stairs, and predominant distal muscle weakness. Skeletal muscle biopsy at age 7 years showed type 1 fiber hypotrophy. Biopsy at age 42 years showed only type 1 fibers, irregularity of fiber size, occasional central nuclei, and peripheral eosinophilic-basophilic densely stained substances consistent with 'caps.' The caps were present in about 10 to 15% of muscle fibers, were negative for ATPase staining, were present just beneath the sarcolemma, and consisted of abnormally arranged myofibrils. Z-lines were thickened with some rod-like structures. The authors noted that this case had first been reported as a congenital myopathy with selective hypotrophy of type 1 fibers (Serratrice et al., 1975), and that the biopsy results discussed in that report would have been consistent with CFTD. The findings suggested a relationship between nemaline myopathy, CFTD, and cap myopathy, and indicated that cap structures may develop over time.
In 4 patients from 2 presumably unrelated Turkish families with autosomal recessive congenital myopathy-4B (CMYO4B; 609284), Lehtokari et al. (2008) identified a homozygous 1-bp deletion (c.913delA, NM_152263) in exon 9b of the TPM3 gene, at the last nucleotide before the stop codon. The mutation was predicted to result in elongation of the protein by 73 residues, which would disrupt the coiled-coil polymer and render the protein nonfunctional. A shared haplotype between the 2 families suggested a founder effect. The phenotype was moderate to severe, with early-onset, restrictive respiratory vital capacity, and chest deformities.
In 5 affected individuals from an Australian family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Clarke et al. (2008) identified a heterozygous c.298C-A transversion (c.298C-A, NM_152263.2) in exon 3 of the TPM3 gene, resulting in a leu100-to-met (L100M) substitution in a highly conserved residue in the alpha-helix domain. Four of the patients presented before age 1 year with hypotonia or decreased activity levels. Two had delayed walking, and all were able to run in the teenage years. The fifth patient presented at age 32 with respiratory failure. Three patients in their forties showed slow walking, impaired nocturnal ventilation, moderate proximal weakness, scapular winging, and ptosis. Two patients had scoliosis. Histologic examination of skeletal muscle showed that type 1 fibers were smaller than type 2 fibers by 50 to 65%, with internal nuclei and no other abnormalities; these findings were consistent with a diagnosis of congenital myopathy with fiber-type disproportion (CFTD).
In a patient with congenital myopathy-4A (CMYO4A; 255310), Clarke et al. (2008) identified a heterozygous c.502C-G transversion (c.502C-G, NM_152263.2) in exon 5 of the TPM3 gene, resulting in an arg168-to-gly (R168G) substitution in the alpha-helix domain. At age 9 years, the patient showed slow running, decreased forced vital capacity, mild proximal muscle weakness, mild ptosis, and lumbar lordosis. Muscle biopsy showed fiber-type disproportion (CFTD).
In a woman with congenital myopathy-4A (CMYO4A; 609284), Clarke et al. (2008) identified a heterozygous c.502C-T transition (c.502C-T, NM_152263.2) in exon 5 of the TPM3 gene, resulting in an arg168-to-cys (R168C) substitution in the alpha-helix domain. The patient had poor head control before 1 year of age, but normal walking at age 9 months, and could run in childhood. At age 32, she could walk stairs with difficulty and had impaired nocturnal ventilation, moderate proximal weakness, ptosis, and severe kyphoscoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD). The authors noted that several other mutations had been identified in this codon (see, e.g., R168G, 191030.0008).
Ohlsson et al. (2009) identified a heterozygous R168C mutation in a 38-year-old woman with CMYO4A associated with cap structures on skeletal muscle biopsy. She had previously been reported by Fidzianska (2002). She had slowly progressive muscle weakness and scoliosis since childhood, but was not examined until age 18 years. At that time, she had long narrow face, high-arched palate, chest deformity, and thin underdeveloped muscles. Other features included impaired nocturnal ventilation. Skeletal muscle biopsy showed that 20 to 30% of muscle fibers had granular cap structures devoid of ATPase activities. Myofibrils forming the caps were clearly demarcated from the remaining fibers and had an abnormal sarcomere pattern. Nemaline rods and fiber-type disproportion were not observed. The findings illustrated the phenotypic and histologic variability associated with TPM3 mutations, and suggested that cap disease is related to nemaline myopathy and CFTD.
Waddell et al. (2010) reported a young man with CMYO4A due to a de novo heterozygous R168C mutation. He had mildly delayed motor development in early childhood, generalized hypotonia, and muscle weakness, particularly of the proximal lower limbs, ankle dorsiflexors, and neck. He had a long myopathic face with open mouth, high-arched palate, retrognathia, narrow chest, and mild scoliosis. At age 20 years, his pulmonary vital capacity was 37% of that predicted. Muscle biopsy taken at age 3 years showed increased variation in fiber size and subsarcolemmal protein inclusions in 25% of fibers, typical of caps. There was also type 1 fiber predominance. Caps stained strongly for several proteins, including tropomyosin, and electron microscopy showed disorganized thin filament structures containing Z-band remnants. Nemaline rods were not present. Two-dimensional gel electrophoresis showed that the mutant protein accounted for about 50% of the TPM3 protein in sarcomeres, and Waddell et al. (2010) postulated a dominant-negative effect, perhaps resulting from altered protein-protein interactions. These findings indicated that the fiber type distribution pattern as well as the pattern of protein inclusions can vary widely even among patients with the same TPM3 mutation.
Malfatti et al. (2013) reported a man of French Canadian origin, with early-onset myopathy and a de novo heterozygous R168C mutation in the TPM3 gene. He had typical clinical features of the disorder, with mildly delayed motor milestones, generalized hypotonia, proximal and distal muscle weakness, impaired respiratory function, long, narrow face, and high-arched palate. Muscle biopsy showed type 1 fiber uniformity, subsarcolemmal caps in about 20% of fibers, typical nemaline rods in about 10% of fibers, and both caps and rods in about 5% of fibers. Electron microscopy demonstrated that the cap structures were composed of disorganized myofibrils and thickened Z-bands; the nemaline rods had longitudinal and transverse striations and were surrounded by thin filaments. Some of the caps contained structures resembling small rods, and the intermyofibrillary network adjacent to caps or nemaline rods was irregular with jagged Z lines. Malfatti et al. (2013) emphasized that the combination of rods and caps had not previously been reported in the same patient, which suggested that the 2 patterns are pathogenetically related. The findings confirmed that nemaline myopathy and cap myopathy resulting from TPM3 mutations are part of a disease spectrum.
In a 5-year-old boy with congenital myopathy-4A (CMYO4A; 609284) characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, Donkervoort et al. (2015) identified a de novo heterozygous 3-bp deletion (c.673_675delGAA, NM_152263.3) in exon 6A of the TPM3 gene, resulting in the deletion of residue glu224 (E224del) in a highly conserved region. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP, Exome Variant Server, or ExAC databases. In vitro studies showed that the mutations resulted in increased calcium sensitivity, increased interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function.
In a 3-year-old girl with congenital myopathy-4A (CMYO4A; 609284) characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, Donkervoort et al. (2015) identified a de novo heterozygous 3-bp deletion (c.657_659delAGA, NM_152263.3) in exon 6A of the TPM3 gene, resulting in the deletion of residue glu218 (E218del) in a highly conserved region. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases. In vitro studies showed that the mutations resulted in increased calcium sensitivity, increased interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function.
In a woman and her son with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Schreckenbach et al. (2014) identified a heterozygous c.445C-A transversion (c.445C-A, NM_152263.2) in exon 4 of the TPM3 gene, resulting in a leu149-to-ile (L149I) substitution. The woman's deceased mother had similar features, but genetic analysis was not performed.
In a 47-year-old man with congenital myopathy-4A (CMYO4A; 255310), Bevilacqua et al. (2022) identified a heterozygous c.709G-A transition in exon 8 of the TPM3 gene, resulting in a glu237-to-lys (E237K) substitution. He had a history of delayed motor development with gait impairment and poor exercise tolerance since childhood. He had no family history of a similar disorder, suggesting that the mutation may have occurred de novo.
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