Alternative titles; symbols
HGNC Approved Gene Symbol: TPM2
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,681,993-35,690,056 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Arthrogryposis, distal, type 1A | 108120 | Autosomal dominant | 3 |
| Arthrogryposis, distal, type 2B4 | 108120 | Autosomal dominant | 3 | |
| Congenital myopathy 23 | 609285 | Autosomal dominant | 3 |
The TPM2 gene encodes beta-tropomyosin, an isoform of tropomyosin that is mainly expressed in slow, type 1 muscle fibers, and, to some extent, in fast muscle fibers and cardiac muscle (summary by Tajsharghi et al., 2007). See also TPM1 (191010), TPM3 (191030), and TPM4 (600317).
Widada et al. (1988) reported the complete nucleotide sequence of the mRNA encoding the human skeletal muscle isoform of beta-tropomyosin. Comparison of this sequence with that of the human fibroblast isoform confirmed that alternative splicing occurs on exons 6 and 9.
Laing et al. (1995) referred to unpublished observations indicating that the TPM2 gene maps to 9p13. Hunt et al. (1995) developed a sequence tagged site (STS) for the TPM2 gene and used it to amplify DNA from somatic cell hybrids to localize the gene to human chromosome 9. The genomic clones isolated with the STS product were in turn used in fluorescence in situ hybridization to metaphase chromosome spreads to refine the localization of TPM2 to 9p13. Tiso et al. (1997) further refined the mapping of the TPM2 gene to 9p13.2-p13.1 using PCR of radiation hybrids.
Stumpf (2022) mapped the TPM2 gene to chromosome 9p13.3 based on an alignment of the TPM2 sequence (GenBank BC011776) with the genomic sequence (GRCh38).
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.
Distal Arthrogryposis Type 1A1
In affected members of a large multigenerational family (family K5) with distal arthrogryposis type 1A1 (DA1A; 108120), originally reported as family F by Bamshad et al. (1994) and linked to the pericentromeric region of chromosome 9, Sung et al. (2003) identified a heterozygous missense mutation in the TPM2 gene (R91G; 190990.0001). The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed. TPM2 mutations were not found in 13 additional probands with a similar disorder.
In in vitro studies, Robinson et al. (2007) demonstrated that the TPM2 R91G mutation resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA1A.
Distal Arthrogryposis Type 2B4
In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see 108120), Tajsharghi et al. (2007) identified a heterozygous mutation in the TPM2 gene (R133W; 190990.0004).
In a Korean mother and daughter with distal arthrogryposis type 2, Ko et al. (2013) identified the same R133W mutation in the TPM2 gene that had previously been identified in an affected mother and daughter (190990.0004).
In a female infant, born to unrelated parents, with congenital distal arthrogryposis, dysmorphic facial features, and myopathy, Mroczek et al. (2017) identified a de novo heterozygous splice site mutation in the TPM2 gene (190990.0011). The mutation was not present in the parents or in 100 healthy controls.
In affected members of a Chinese family (family 1) segregating DA2B4, Li et al. (2018) identified heterozygosity for a missense mutation (Q103R; 190990.0010) in the TPM2 gene.
Congenital Myopathy 23
In 2 unrelated patients with congenital myopathy-23 (CMYP23; 609285), a woman with a mild form of the disease and the son of an affected mother, Donner et al. (2002) identified 2 different heterozygous missense mutations in the TPM2 gene (Q147P, 190990.0002 and E117K, 190990.0003, respectively). The affected mother was found to carry the same mutation as her son. Functional studies of the variants were not performed, but the authors speculated that the mutation affects the actin-binding properties of TPM2.
In a 36-year-old man with CMYP23 since childhood, Lehtokari et al. (2007) identified a heterozygous 3-bp in-frame deletion (415delGAG; 190990.0006) of the TPM2 gene, resulting in the removal of glu139 and predicted to disrupt the 7-amino acid repeat essential for making a coiled-coil motif and to impair tropomyosin-actin interaction. Clarke et al. (2009) identified the E139del mutation in a girl with cap myopathy. Protein studies showed that the mutant TPM2 protein interacted with the wildtype protein and was incorporated into the sarcomere. The authors postulated that the mutation probably weakened the interaction with other proteins within skeletal muscle.
Ohlsson et al. (2008) identified 3 different heterozygous TPM2 mutations (see, e.g., 190990.0007 and 190990.0008) in 3 unrelated patients with CMYP23. One of the mutations deleted residue K49 (190990.0007). Functional studies of the variants were not performed.
In 8 patients from 5 unrelated families with CMYP23, Mokbel et al. (2013) identified the same 3-bp deletion in the TPM2 gene (lys7del, K7del; 190990.0009). The transmission pattern in 2 families was consistent with autosomal dominant inheritance; the mutation was suspected to have occurred de novo in 3 other families. Studies of patient muscle and differentiated myotubes transfected with the mutation suggested that the mutant protein incorporates poorly into sarcomeres and likely accumulates in nemaline bodies, and interferes with wildtype in a dominant-negative manner. Patient myofibers had normal force generation, but increased sensitivity to calcium in motility assays. The mutant protein also showed reduced binding affinity for actin and a decreased ability to polymerize into long tropomyosin filaments. Mokbel et al. (2013) noted that the presence of joint contractures was the most prominent clinical feature in these patients and that 1 patient had hypertonicity. These findings suggested that the joint contractures may result from impaired muscle relaxation and a tendency for muscles to slowly shorten. Progressive muscle weakness in adulthood may result from a combination of muscle degeneration and apoptosis due to cellular stress.
Davidson et al. (2013) identified a heterozygous K7del mutation in affected members of 4 families with CMYP23 associated with distal arthrogryposis and limited jaw opening. The mutation in 1 family was found by whole-exome sequencing and confirmed by Sanger sequencing to segregate with the disorder; the mutation in the other families was found by candidate gene testing. Molecular modeling predicted that the mutation would alter protein-protein binding between TPM2 and other proteins as well as disturb the head-to-tail polymerization of TPM2 dimers. Expression of the mutation in developing zebrafish showed that the mutant protein did not localize properly within the thin filament compartment and altered sarcomere length, suggesting that it impaired sarcomeric structure. Areas of perimembranous accumulations of alpha-actinin were observed in mutant myofibers, consistent with findings in nemaline myopathy. These findings unified the phenotype of congenital myopathy with distal arthrogryposis (DA1A; 108120).
In in vitro studies, Marston et al. (2013) found that certain TPM2 mutations affecting the actin binding sites, K49del (190090.0007), R91G (190090.0001), E139del (190090.0006), E181K, and K168E, resulted in higher calcium sensitivity, higher filament sliding speeds, and a gain-of-function effect. In contrast, the E41K (190090.0005) and E117K (190090.0003) mutations showed lower calcium sensitivity, slower sliding speeds, and a hypocontractile phenotype. Marston et al. (2013) noted the range of muscle biopsy findings identified in patients with these mutations and suggested that consideration of the effects of the mutations on muscle contractility would be more predictive of the phenotype. Specifically, patients with gain-of-function mutations tended to have hypercontractility associated with arthrogryposis. 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).
In affected members of a large multigenerational family with distal arthrogryposis type 1 (DA1; 108120) originally reported by Bamshad et al. (1994) and linked to the pericentromeric region of chromosome 9, Sung et al. (2003) identified a heterozygous c.271C-G transversion in exon 3 of the TPM2 gene, resulting in an arg91-to-gly (R91G) substitution at a highly conserved residue. The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed.
In in vitro studies, Robinson et al. (2007) demonstrated that the R91G mutation resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Structurally, the R91G mutation disrupted both actin binding and coiled-coil stability. Robinson et al. (2007) concluded that in patients the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb defects via an active process rather than a passive process.
In 1 of 66 unrelated patients with congenital myopathy-23 (CMYP23; 609285), Donner et al. (2002) identified a heterozygous A-to-C transversion in exon 4 of the TPM2 gene, resulting in a gln147-to-pro (Q147P) substitution. The affected Dutch woman had a mild form of the disorder, presenting at age 12 years with difficulty walking. Muscle biopsy showed type 1 fiber predominance and aggregates of rods. There was no family history of the disorder. The mutation was not identified in 100 control individuals. Donner et al. (2002) speculated that the mutation affects the actin-binding properties of beta-tropomyosin.
In a Bosnian mother and son with presumed congenital myopathy-23 (CMYP23; 609285), Donner et al. (2002) identified a heterozygous G-to-A transition in exon 3 of the TPM2 gene, resulting in a glu117-to-lys (E117K) substitution. The boy presented with feeding difficulties and severe hypotonia at birth. He had delayed motor milestones, but achieved ambulation. His mother had never been able to run, had myopathic facies and a high-arched palate, and asymmetric limb involvement. One muscle biopsy from the son showed type 1 fiber predominance consistent with nemaline myopathy, but the finding of nemaline rods was equivocal; however, Donner et al. (2002) noted that the quantity of nemaline rods can vary substantially in affected patients. The mutation was not identified in 100 control individuals. The authors speculated that the mutation affects the actin-binding properties of beta-tropomyosin.
In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see 108120), Tajsharghi et al. (2007) identified a heterozygous 5396C-T transition in exon 4 of the TPM2 gene, resulting in an arg133-to-trp (R133W) substitution. At the time of the report, the mother and daughter were 65 and 28 years, respectively. Both had presented with distal joint contractures at birth. At the time of examination, both complained of muscle weakness in proximal and distal muscles, most prominent in the hands and feet. Other notable features in both patients included hearing impairment, high-arched palate, short neck, short stature, contractures in proximal joints, smooth palms, and scoliosis. Neither had cardiac involvement.
In a Korean mother and daughter with DA2B4, Ko et al. (2013) identified heterozygosity for the R133W mutation in the TPM2 gene.
In a mother and daughter with congenital myopathy-23 (CMYP23; 609285), Tajsharghi et al. (2007) identified a heterozygous 360G-A transition (c.360G-A, NM-213674) in exon 2 of the TPM2 gene, resulting in a glu41-to-lys (E41K) substitution.
In a 36-year-old man with congenital myopathy-23 (CMYP23; 609285) since childhood, Lehtokari et al. (2007) identified a heterozygous 3-bp in-frame deletion (c.415delGAG, ENST00000329305) in exon 4 of the TPM2 gene, resulting in the removal of glu139 and predicted to disrupt the 7-amino acid repeat essential for making a coiled-coil motif and to impair tropomyosin-actin interaction. The patient had delayed motor development, was never able to run, showed generalized muscle weakness, and had additional features, including hyperlordosis, ptosis, and high-arched palate.
Clarke et al. (2009) reported a 14-year-old Australian girl with CMYP23 who was heterozygous for the 415delGAG deletion (c.415delGAG, NM_003289). She had a history of hypotonia since infancy, delayed motor development, and slow running. She had generalized muscle wasting and weakness, particularly in the proximal muscles, and hyporeflexia. Other features included mild facial weakness, nasal voice, high-arched palate, long thin face, and mild micrognathia. Cardiac examination showed decreased systolic function, with an ejection fraction of 42%, mild mitral valve prolapse, and borderline aortic root dilatation. She also had central hypoventilation and restrictive lung disease with decreased forced vital capacity, and developed thoracic scoliosis in her teens. Skeletal muscle biopsy at age 10 showed fiber type variability, and she received an initial diagnosis of congenital fiber-type disproportion, a diagnosis of exclusion. However, about 4% of fibers were later noted to have caps, leading to a final histologic diagnosis of cap myopathy. There was type 1 fiber predominance. Electron microscopy showed irregular and thickened Z-lines, and the caps contained disorganized thin filaments. No classic nemaline rods were observed. Protein studies showed that the mutant TPM2 protein interacted with the wildtype protein and was incorporated into the sarcomere. The authors postulated that the mutation probably weakened the interaction with other proteins within skeletal muscle. Clarke et al. (2009) noted that the cardiac involvement in this patient was an unusual finding.
In a 42-year-old man with congenital myopathy-23 (CMYP23; 609285) and symptoms of muscle weakness since childhood, Ohlsson et al. (2008) identified a de novo heterozygous in-frame 3-bp deletion (c.384delGAA, NM_003289) in exon 2 of the TPM2 gene, resulting in the deletion of lys49. By age 15 years, he required a wheelchair when outdoors, but the disorder was no longer progressive in adulthood. He had diffuse, symmetric muscle weakness and wasting, kyphoscoliosis, high-pitched voice, and decreased pulmonary vital capacity. Muscle biopsy showed uniformity of type 1 fibers, cap structures with disorganized myofibrils, and an irregular intermyofibrillar network.
In an 8-year-old girl with a severe form of congenital myopathy-23 (CMYP23; 609285), Ohlsson et al. (2008) identified a de novo heterozygous 845C-G transversion (c.845C-G, NM_003289) in the TPM2 gene, resulting in an asn202-to-lys (N202K) substitution in the putative troponin T-binding region. The patient had reduced fetal movements in utero and was hypotonic at birth. She had severe muscle weakness in the face and axial muscles and severe respiratory compromise necessitating mechanical ventilation. Muscle biopsy showed uniformity of type 1 fibers, cap structures, and a coarse intermyofibrillar network.
In 8 patients from 5 unrelated families with congenital myopathy-23 (CMYP23; 609285), Mokbel et al. (2013) identified a heterozygous 3-bp deletion (c.19_21delAAG) in exon 1 of the TPM2 gene, resulting in the deletion of residue lys7 (K7del), which is 1 of 3 highly conserved lysine residues at the N terminus. The transmission pattern in 2 families was consistent with autosomal dominant inheritance; the mutation was suspected to have occurred de novo in 3 other families. The mutation was not found in the Exome Variant Server database. Studies of patient muscle and differentiated myotubes transfected with the mutation suggested that the mutant protein incorporates poorly into sarcomeres and likely accumulates in nemaline bodies, and interferes with wildtype protein in a dominant-negative manner. Patient myofibers had normal force generation, but increased sensitivity to calcium in motility assays. The mutant protein also showed reduced binding affinity for actin and a decreased ability to polymerize into long tropomyosin filaments. Mokbel et al. (2013) noted that the presence of joint contractures was the most prominent clinical feature in these patients and that 1 patient had hypertonicity. These findings suggested that the joint contractures may result from impaired muscle relaxation and a tendency for muscles to slowly shorten. Progressive muscle weakness in adulthood may result from a combination of muscle degeneration and apoptosis due to cellular stress.
Davidson et al. (2013) identified a heterozygous K7del mutation, which they stated resulted from c.20_22del, in affected members of 4 families with a phenotype consistent with nemaline myopathy. Common clinical features in the families included muscle weakness and the presence of early distal extremity contractures combined with trismus. These findings unified the phenotype of congenital myopathy with distal arthrogryposis (DA1A; 108120). The mutation in 1 family was found by whole-exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in an in-house exome database. The mutation in the other families was found by candidate gene testing. Molecular modeling predicted that the mutation would alter protein-protein binding between TPM2 and other proteins as well as disturb the head-to-tail polymerization of TPM2 dimers. Expression of the mutation in developing zebrafish showed that the mutant protein did not localize properly within the thin filament compartment and altered sarcomere length, suggesting that it impaired sarcomeric structure. Areas of perimembranous accumulations of alpha-actinin were observed in mutant myofibers, consistent with findings in nemaline myopathy.
In affected members of a Chinese family (family 1) segregating distal arthrogryposis type 2B4 (DA2B4; see 108120), Li et al. (2018) identified heterozygosity for a c.308A-G transition in exon 3 of the TPM2 gene, resulting in a gln103-to-arg (Q103R) substitution at a highly conserved residue. The mutation, which was found by linkage analysis and Sanger sequencing, was not found in the ExAC, gnomAD, ESP6599, 1000 Genomes Project, and dbSNP databases. Molecular modeling indicated that the mutation may impair protein function.
In a female infant, born to unrelated parents, with congenital distal arthrogryposis, facial dysmorphism, and myopathy (DA2B4; see 108120), Mroczek et al. (2017) identified a de novo heterozygous splice site mutation (c.374+2T-C) in the TPM2 gene. The mutation resulted in an aberrantly spliced transcript containing intron 3 and a frameshift mutation resulting in a premature stop codon. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the unaffected parents or in 100 control individuals.
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