HGNC Approved Gene Symbol: TPM4
Cytogenetic location: 19p13.12-p13.11 Genomic coordinates (GRCh38) : 19:16,067,538-16,103,002 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.12-p13.11 | Bleeding disorder, platelet-type, 25 | 620486 | Autosomal dominant | 3 |
Wilton et al. (1996) developed sequence tagged sites (STS) for the TPM4 gene.
Pleines et al. (2017) showed that TPM4 localized to proplatelets and colocalized with filamentous actin in primary CD34+ human megakaryocytes. Knockdown of TPM4 in these cells did not affect megakaryocyte proliferation or maturation, but impaired proplatelet formation.
Vertebrates have at least 4 different tropomyosin genes; in humans, they are named TPM1 (191010), TPM2 (190990), TPM3 (191030), and TPM4. Both the muscle and nonmuscle isoforms of the tropomyosins are expressed through alternative splicing of each of the 4 genes (summary by Laing et al., 1995).
Laing et al. (1995) referred to unpublished observations indicating that the TPM4 gene maps to human chromosome 19.
Using an STS corresponding to the TPM4 gene to amplify DNA from somatic cell hybrids, Wilton et al. (1996) localized the TPM4 gene to chromosome 19. Another STS, a product from a long-range PCR, was used directly as a probe to refine the localization of TPM4 to 19p13.1 by fluorescence in situ hybridization to metaphase chromosome spreads.
In 5 patients from 2 unrelated families with platelet-type bleeding disorder-25 (BDPLT25; 620486), Pleines et al. (2017) identified a heterozygous nonsense mutation in the TPM4 gene (R69X; 600317.0001). The mutation, which was found by genome sequencing, segregated with the phenotype in the families and was not present in the ExAC database. Patient-derived platelets showed about a 50% decrease in TPM4 mRNA and protein levels, suggesting that the mutation resulted in a loss of function. Patient-derived platelets showed morphologic abnormalities and mild functional defects. Additional studies indicated that the mutation resulted in defects in the terminal stages of platelet biogenesis from megakaryocytes, likely due to disruption of actin cytoskeletal dynamics. The 2 probands were identified from a cohort of 865 index cases with bleeding and platelet disorders who underwent genome sequencing.
In a mother and daughter with BDPLT25, Stapley et al. (2022) identified a heterozygous missense mutation in the TPM4 gene (R182C; 600317.0002). The mutation, which was found by sequencing of a targeted gene panel and confirmed by Sanger sequencing, was present in 2 of 246,478 alleles in gnomAD. Patient platelets showed decreased spreading on fibrinogen, reduced granule content, enlarged vacuoles, variably impaired aggregation responses to agonists, and secretion defects. TPM4 protein levels were normal, but patient platelets showed disordered TPM4 staining. The mother had a normal platelet count, whereas the daughter had mild thrombocytopenia; both had enlarged platelets. Marin-Quilez et al. (2022) postulated that missense mutations in TPM4 may have a dominant-negative effect, whereas nonsense mutations result in haploinsufficiency.
In 5 members of a 2-generation Spanish family with BDPLT25, Marin-Quilez et al. (2022) identified a heterozygous nonsense mutation in the TPM4 gene (Q108X; 600317.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Platelet lysates from the mutation carriers showed decreased TPM4 protein levels, suggesting haploinsufficiency. Platelet functional studies showed a reduction in the formation of filopodia and lamellipodia, impaired platelet spreading. Mutant TPM4 accumulated abnormally mainly in the center of the platelets and had reduced localization with other cytoskeletal proteins.
Pleines et al. (2017) identified a mutant mouse strain (Plt53) with dominant macrothrombocytopenia associated with a heterozygous loss-of-function mutation in the Tpm4 gene. Homozygous mutant animals had more severe thrombocytopenia, consistent with a dose-dependent effect. Otherwise, the mutant mice were healthy and fertile. Bone marrow from homozygous mutant mice showed normal numbers of megakaryocyte precursors, although megakaryocytes were increased and showed abnormal morphology with impaired proplatelet formation. Additional studies showed disturbance of regulators of the megakaryocyte actin cytoskeleton important for megakaryocyte branching and proplatelet formation. Platelets derived from mutant animals showed heterogeneity in platelet size and frequent vacuoles, indicating increased platelet fragility. There were also functional platelet defects, including delayed spreading on fibrinogen and reduced thrombus formation. Mutant mice had mildly increased bleeding time.
In 5 patients from 2 unrelated families with platelet-type bleeding disorder-25 (BDPLT25; 620486), Pleines et al. (2017) identified a heterozygous C-to-T transition (chr19.16,192,795C-T, GRCh37) in exon 3 of the TPM4 gene, resulting in an arg69-to-ter (R69X) substitution in the major protein isoform TPM4.2. The mutation, which was found by genome sequencing, segregated with the phenotype in the families and was not present in the ExAC database. Patient-derived platelets showed about a 50% decrease in TPM4 mRNA and protein levels, suggesting that the mutation resulted in a loss of function. The 2 probands were identified from a cohort of 865 index cases with bleeding and platelet disorders who underwent genome sequencing. Stapley et al. (2022) referred to this mutation as R105X; Pleines et al. (2017) noted that this numbering corresponds to the minor isoform TPM4.1.
In a mother and daughter (P1 and P2) with platelet-type bleeding disorder-25 (BDPLT25; 620486), Stapley et al. (2022) identified a heterozygous c.544C-T transition (c.544C-T, NM_001145160.1) in the TPM4 gene, resulting in an arg182-to-cys (R182C) substitution at a highly conserved residue in the tropomyosin domain. The mutation, which was found by sequencing of a targeted gene panel and confirmed by Sanger sequencing, was present in 2 of 246,478 alleles in gnomAD. Patient platelets showed decreased spreading on fibrinogen, reduced granule content, enlarged vacuoles, variably impaired aggregation responses to agonists, and secretion defects. TPM4 protein levels were normal, but patient platelets showed disordered TPM4 staining. The mother had a normal platelet count, whereas the daughter had mild thrombocytopenia; both had enlarged platelets.
In 5 members of a 2-generation Spanish family with platelet-type bleeding disorder-25 (BDPLT25; 620486), Marin-Quilez et al. (2022) identified a heterozygous c.322C-T transition (c.322C-T, NM_003290.3) in exon 3 of the TPM4 gene, resulting in a gln108-to-ter (Q108X) substitution in the coiled-coil domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Platelet lysates from the mutation carriers showed decreased TPM4 protein levels, suggesting haploinsufficiency. Platelet functional studies showed a reduction in the formation of filopodia and lamellipodia, impaired platelet spreading. Mutant TPM4 accumulated abnormally mainly in the center of the platelets and had reduced localization with other cytoskeletal proteins.
Laing, N. G., Wilton, S. D., Akkari, P. A., Dorosz, S., Boundy, K., Kneebone, C., Blumbergs, P., White, S., Watkins, H., Love, D. R., Haan, E. A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nature Genet. 9: 75-79, 1995. Note: Erratum: Nature Genet. 10: 249 only, 1995. [PubMed: 7704029] [Full Text: https://doi.org/10.1038/ng0195-75]
Marin-Quilez, A., Vuelta, E., Diaz-Ajenjo, L., Fernandez-Infante, C., Garcia-Tunon, I., Benito, R., Palma-Barqueros, V., Hernandez-Rivas, J. M., Gonzalez-Porras, J. R., Rivera, J., Bastida, J. M. A novel nonsense variant in TPM4 caused dominant macrothrombocytopenia, mild bleeding tendency and disrupted cytoskeleton remodeling. J. Thromb. Haemost. 20: 1248-1255, 2022. [PubMed: 35170221] [Full Text: https://doi.org/10.1111/jth.15672]
Pleines, I., Woods, J., Chappaz, S., Kew, V., Foad, N., Ballester-Beltran, J., Aurbach, K., Lincetto, C., Lane, R. M., Schevzov, G., Alexander, W. S., Hilton, D. J., and 18 others. Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. J. Clin. Invest. 127: 814-829, 2017. [PubMed: 28134622] [Full Text: https://doi.org/10.1172/JCI86154]
Stapley, R. J., Poulter, N. S., Khan, A. O., Smith, C. W., Bignell, P., Fratter, C., Lester, W., Lowe, G., Morgan, N. V., UK GAPP Study Group. Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding. J. Thromb. Haemost. 20: 478-485, 2022. Note: Erratum: J. Thromb. Haemost. 20: 1511 only, 2022. [PubMed: 34758189] [Full Text: https://doi.org/10.1111/jth.15584]
Wilton, S. D., Lim, L., Dorosz, S. D., Gunn, H. C., Eyre, H. J., Callen, D. F., Laing, N. G. Assignment of the human alpha-tropomyosin gene TPM4 to band 19p13.1 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 72: 294-296, 1996. [PubMed: 8641132] [Full Text: https://doi.org/10.1159/000134206]