Disease relevance of TPM1

• De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy [1].
• BACKGROUND: We report hypertrophic cardiomyopathy (HCM) in a Spanish-American family caused by a novel alpha-tropomyosin (TPM1) mutation and examine the pathogenesis of the clinical disease by characterizing functional defects in the purified mutant protein [2].
• CONCLUSIONS: The novel mutation identified in TPM1 is associated with the clinical features of cardiac hypertrophy in all but one genetically affected member of this large family [3].
• A novel TPM1 mutation in a family with hypertrophic cardiomyopathy and sudden cardiac death in childhood [4].
• Thus, a novel missense mutation in TPM1 was discovered in a family with HC and sudden death in childhood [4].

Psychiatry related information on TPM1

• TMSA, a variant of TMSSA, was very similar to TMSSA except for its greater frequency in cerebrovascular disorders without dementia [5].

High impact information on TPM1

• Mutations in five different loci cause FHC and 3 disease genes have been identified: beta cardiac myosin heavy chain, alpha tropomyosin and cardiac troponin T. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sarcomere components [6].
• A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy [7].
• Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy [8].
• The mutation substitutes an arginine residue for a highly conserved methionine in a putative actin-binding site near the N terminus of the alpha-tropomyosin [7].
• We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2 [9].

Biological context of TPM1

• Forced expression of TPM1 by using Tet-Off system increased stress fibers in MDA-MB-231 cells and reduced cell migration [10].
• Bisulfite sequencing showed significant cytosine methylation in metastatic cell lines that correlated with a reduced expression of TPM1 [10].
• The TPM1 isoform specific to striated muscle, designated TPM1alpha, consists of 10 exons: 1a, 2b, 3, 4, 5, 6b, 7, 8, and 9a/b. In this study, using RT-PCR with adult and fetal human RNAs, we present evidence for the expression of a novel isoform of the TPM1 gene that is specifically expressed in cardiac tissues [11].
• However, no mutations were found in the protein-coding region of TPM1, although small deletions or mutations in an intron cannot be excluded [12].
• Fluorescence in situ hybridization of this clone to metaphase chromosome spreads localised TPM1 to chromosome band 15q22 [13].

Anatomical context of TPM1

• RT-PCR analysis in carcinoma cell lines revealed a significant reduction in TPM1 transcripts in metastatic MDA-MB-231, MDA-MB-435 and SW620 cell lines [10].
• TGF-beta induction of stress fibers in epithelial cells requires high molecular weight tropomyosins encoded by TPM1 and TPM2 genes [10].
• Among these mRNAs, alpha-tropomyosin (alpha-TM) is known to exhibit a muscle cell type-specific splicing pattern [14].
• The first 188 amino acids of Tm3 are identical to those of rat or rabbit skeletal muscle alpha-tropomyosin, and the last 71 amino acids differ from those of rat smooth muscle alpha-tropomyosin by only 1 residue [15].
• No alpha-tropomyosin-related RNAs are abundant in undifferentiated myoblasts [16].

Associations of TPM1 with chemical compounds

• Treatment of these cells with demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) increased mRNA levels of TPM1 with no effect on TPM2 [10].
• Role of an inhibitory pyrimidine element and polypyrimidine tract binding protein in repression of a regulated alpha-tropomyosin exon [17].
• These studies have revealed that the amino acid sequence of human cardiac alpha tropomyosin is identical to that of the rabbit skeletal alpha tropomyosin, but for a single conservative substitution of Arg/Lys at position 220 [18].
• Here we show that a 35-kDa member of the SR protein family, 9G8, can activate the splicing of alpha-tropomyosin exon 2 [19].
• The ability of these peptides to form two-stranded alpha-helical coiled-coils in benign medium (1.1 M KC1, 0.05 M PO4 buffer, pH 7.0) was monitored by molecular weight determinations and circular dichroism studies and their physical properties were compared to carboxamidomethylated alpha-tropomyosin at cysteine 190 (CM-tropomyosin) [20].

Physical interactions of TPM1

• This study was initiated with exons 9 and 11 of TNNT2 because of their crucial role in the binding ability of cardiac troponin T to alpha-tropomyosin, and continued with analyses in other regions of the gene [21].
• The 65-kDa protein bound to the G+U-rich NRE 3' half which shows homology to the B2P2 sequence a known U2AF65 binding site in the alpha-tropomyosin gene, and the G+U-rich element can be replaced by B2P2 in the binding assay [22].

Regulatory relationships of TPM1

• Exon selection in alpha-tropomyosin mRNA is regulated by the antagonistic action of RBM4 and PTB [14].

Other interactions of TPM1

• Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast [23].
• Altogether, the aforementioned 6 mutations found in MYBPC3, TPM1, and MYH7 accounted for 61% of familial and 40% of all HCM cases [24].
• DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing [25].
• Together these results suggest that epigenetic suppression of TPM1 may alter TGF-beta tumor suppressor function and contribute to metastatic properties of tumor cells [10].
• A potential CpG island spanning the TPM1 proximal promoter, exon 1, and the beginning of intron 1 was identified [10].
• We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283 [26].

Analytical, diagnostic and therapeutic context of TPM1

• We have searched for mutations in alpha-tropomyosin gene in 50 Japanese patients with hypertrophic cardiomyopathy (HCM) by means of polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis [27].
• The transgenic proteins were stably integrated into the sarcomere, as shown by immunohistochemistry using a human-specific anti-alpha-tropomyosin antibody, ARG1 [28].
• PURPOSE: To assess first-pass magnetic resonance (MR) imaging in the evaluation of perfusion impairment in a genetically homogeneous population of patients with hypertrophic cardiomyopathy (HCM) and the Asp175Asn mutation of the alpha-tropomyosin gene and to evaluate the association between hypertrophy and perfusion [29].
• Using gel mobility shift assays, we show that formation of stable enhancer-specific complexes on alpha-tropomyosin exon 2 requires the presence of both SR proteins and the 110-kD protein [30].
• Differential scanning calorimetry was used to investigate the thermal unfolding of native alpha-tropomyosin (Tm), wild-type alpha-Tm expressed in Escherichia coli and the wild-type alpha-Tm carrying either of two missense mutations associated with familial hypertrophic cardiomyopathy, D175N or E180G [31].

References