HGNC Approved Gene Symbol: TNNI2
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:1,838,981-1,841,678 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Arthrogryposis, distal, type 2B1 | 601680 | Autosomal dominant | 3 |
Troponin I (TnI) is a myofibrillar protein involved in the calcium-mediated regulation of striated muscle contraction. Three isoforms of troponin I are known and each is expressed in a muscle fiber-type-specific manner. TnI-fast (TNNI2) and TnI-slow (TNNI1; 191042) are expressed exclusively in fast-twitch and slow-twitch skeletal muscle myofibers, respectively, while TnI-card (TNNI3; 191044), a cardiac muscle isoform (TNNI3; 191044), is expressed in both the atrium and ventricle of the heart (summary by Wade et al., 1990).
Zhu et al. (1994) isolated the human troponin I fast-twitch isoform from a skeletal muscle cDNA library. The TnI(fast) gene encodes a predicted 182-amino acid protein that is 59% similar to TNNI1 and 57% similar to TNNI3, with most of the sequence divergence in the amino-terminal half of the proteins. The human TnI(fast) protein sequence is 97% homologous to that of the homologous mouse gene.
Cartilage is an avascular and relatively tumor-resistant tissue. The process of new capillary formation, or angiogenesis, is an essential component of a number of serious pathologic states, including solid tumor growth and metastasis, diabetic retinopathy, rheumatoid arthritis, and others. Given the potential therapeutic benefit that an angiogenesis inhibitor could have in the treatment of these disorders, suppressors of neovascularization have been sought. This work has demonstrated that cartilage is an enriched source of endogenous inhibitors of angiogenesis. Moses et al. (1999) identified a novel cartilage-derived inhibitor of new capillary growth. By peptide microsequencing and protein database analysis, they identified the purified inhibitory protein as troponin I(fast), a subunit of the troponin complex (troponin C (see 191039) and troponin T (see 600692) being the other 2), which, along with tropomyosin (191010), is responsible for the calcium-dependent regulation of striated muscle contraction. Independently, troponin I(fast) is capable of inhibiting actomyosin ATPase. The discovery that a contractile protein such as this is present in nonmuscle tissues, although novel with respect to cartilage, was not unprecedented with respect to other nonmuscle tissues. The presence of a number of contractile proteins, including troponin C, actin (see 102610), tropomyosin, myosin heavy chain (see 160730), and dystrophin (see 300377), has been demonstrated in nonmuscle tissues, where they may serve a function in processes other than mediating and regulating contraction of striated muscle.
Guenet et al. (1996) demonstrated that the Tnni2 gene maps to mouse chromosome 7. Tnni3 also maps to mouse chromosome 7 in a proximal portion. The region of mouse chromosome 7 that carried the Tnni2 locus was syntenic with portions of human chromosomes 10 and 11.
By PCR analysis of radiation hybrids, Tiso et al. (1997) mapped the TNNI2 gene to 11p15.5, near the TNNT3 gene (600692). Using somatic cell hybrid analysis with monochromosomal and radiation hybrid panels, Barton et al. (1997) mapped the TNNI2 gene to 11p15.5.
Barton et al. (1997) pointed out that the findings of mapping studies indicate that the troponin I and T genes are organized in pairs on 3 separate chromosomes: TNNI1 and TNNT2 (191045) are located on 1q32. TNNI2 and TNNT3 are located on 11p15.5. TNNI3 and TNNT1 (191041) are located on 19q13.4. These findings suggest that the troponin genes are derived from triplication of a locus containing an ancestral troponin I/troponin T gene pair, resulting in 3 paralogous chromosomal regions (Lundin, 1993). They noted that in both Drosophila and C. elegans the single troponin I and troponin T genes are located on the same chromosome. Close physical linkage of the human genes may have implications for the analysis of mutations in a hereditary disease, such as familial hypertrophic cardiomyopathy. Exclusion of the second troponin gene as a possible cause may be a necessary precaution. Future studies of the troponin I/T gene pairs may reveal whether linkage is important for their regulation.
Sung et al. (2003) reported that distal arthrogryposis type 2B (DA2B1; 601680) is caused by mutations in the TNNI2 gene (191043.0001). Sung et al. (2003) screened 14 individuals with classic Freeman-Sheldon syndrome (FSS; 193700) for mutations in TNNI2 and found no variation that could be construed as disease-causing.
Jiang et al. (2006) identified a heterozygous mutation in the TNNI2 gene (191043.0003) in affected members of a large Chinese family with DA2B.
In in vitro studies, Robinson et al. (2007) demonstrated that the TNNI2 R174Q (191043.0001) and R156X (191043.0002) mutations 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 in patients 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 DA2B.
In affected members of a family with DA2B, Li et al. (2013) identified a heterozygous missense mutation in the TNNI2 gene (I165F; 191043.0006). The mutation segregated with the phenotype in the family.
In 2 unrelated families from among 34 kindreds with distal arthrogryposis type 2B (DA2B1; 601680), Sung et al. (2003) found a G-to-A transition at nucleotide 521 that caused an arginine174-to-glutamine substitution (R174Q). This change was considered to be disease-causing because the change involved an amino acid residue that is highly conserved in all isoforms of TNNI and between mice and humans, and because it was found in 2 unrelated families but not in 140 control chromosomes. Furthermore, the R174Q missense mutation arose de novo and caused DA2B1 in all of the children who inherited it.
In 2 unrelated families, Sung et al. (2003) found that type 2B distal arthrogryposis (DA2B1; 601680) was caused by a 466C-T transition in exon 8 of the TNNI2 gene, resulting in a mutant TnI lacking 26 amino acid residues at the carboxy terminus (arg156-to-ter; R156X). In 1 kindred this mutation arose de novo in the affected father and was subsequently transmitted to all of his offspring, each of whom was affected and had a different mother. The segregation of the mutation in the second kindred suggested either that it arose de novo twice or that mosaicism for this mutation existed in 1 of the phenotypically normal parents. However, the level of mosaicism may have been too low to be detected in lymphocytes and/or may have existed in cell populations that were not tested (e.g., gonadal tissue).
Drera et al. (2006) identified a heterozygous R156X mutation in an Italian mother and son with DA2B1. The authors noted that the C terminus of TnI plays a role in conferring Ca(2+) sensitivity and actin affinity, suggesting that the mutant protein lacks the ability to inhibit muscle contraction in the absence of Ca(2+).
In 5 affected members of a 3-generation Swedish family with distal arthrogryposis type 2B (DA2B1; 601680), Kimber et al. (2006) identified a heterozygous 3-bp in-frame deletion (526delAAG) in exon 8 of the TNNI2 gene, resulting in the skipping of a highly conserved lys176 residue in the C-terminal region. Four affected adults had increased serum creatine kinase and mild myopathic changes associated with type 2 muscle fibers on muscle biopsy. However, muscle weakness was not apparent in these individuals. Kimber et al. (2006) postulated that the phenotype may be due to improper muscle relaxation, decreased fetal movements, and resultant arthrogryposis as well as disturbed regulation of muscle contraction.
In 9 affected members of a large Chinese family with distal arthrogryposis type 2B1, Jiang et al. (2006) identified a heterozygous 3-bp deletion in exon 8 of the TNNI2 gene, which they reported as 523delAAG, resulting in deletion of the lys175 residue. The mutation was not detected in unaffected family members or in 50 control individuals. There was marked phenotypic variability ranging from mild camptodactyly only to severe hand and foot malformation with facial anomalies.
In 6 affected members of a 3-generation family with distal arthrogryposis type 2B (DA2B1; 601680), Shrimpton and Hoo (2006) identified a heterozygous 3-bp in-frame deletion (496delGAG) in the TNNI2 gene, resulting in loss of the highly conserved residue glu167 in the C terminus. The phenotype was variable among family members.
In affected members of a Chinese family with distal arthrogryposis (DA2B1; 601680), Li et al. (2013) identified heterozygosity for a c.493A-T transversion in the TNNI2 gene, resulting in an ile165-to-phe (I165F; 191043.0006) substitution. The mutation segregated with the phenotype in the family. The variant was not found in the dbSNP (build 132) or 1000 Genomes Project databases or in 200 control chromosomes. The authors stated that the mutation occurs in the C-terminal region, which is critical for proper protein function. Although the authors diagnosed the patients with DA2B1 (601680), they noted that many typical features of DA2B1 were not present in the patients.
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Drera, B., Zoppi, N., Barlati, S., Colombi, M. Recurrence of the p.R156X TNNI2 mutation in distal arthrogryposis type 2B. (Letter) Clin. Genet. 70: 532-534, 2006. [PubMed: 17101001] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00713.x]
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Jiang, M., Zhao, X., Han, W., Bian, C., Li, X., Wang, G., Ao, Y., Li, Y., Yi, D., Zhe, Y., Lo, W. H. Y., Zhang, X., Li, J. A novel deletion in TNNI2 causes distal arthrogryposis in a large Chinese family with marked variability of expression. Hum. Genet. 120: 238-242, 2006. [PubMed: 16802141] [Full Text: https://doi.org/10.1007/s00439-006-0183-4]
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Li, X., Jiang, M., Han, W., Zhao, N., Liu, W., Sui, Y., Lu, Y., Li, J. A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures. Gene 527: 630-635, 2013. [PubMed: 23850728] [Full Text: https://doi.org/10.1016/j.gene.2013.06.082]
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