Abstract
Background
Arthrogryposis is a medical term used to describe congenital contractures which often affect multiple limbs. Distal arthrogryposis (DA) is one of the major categories of arthrogryposis that primarily affects the distal parts of the body, i.e., the hands and the legs. Although ten different types and several subtypes of DAs have been described, the genes associated with each of these DAs are yet to be characterized. Distal arthrogryposis type 10 (DA10) is a rare genetic disease, which is distinguished from the other arthrogryposis types by plantar flexion contractures resulting in toe-walking during infancy as well as variability in contractures of the hip, hamstring, elbow, wrist and finger joints with no ocular or neurological abnormalities. Symptoms of DA10 indicate impairment specifically in the musculoskeletal system. DA10 is still poorly studied.
Aim
The objective of this study was to identify the candidate gene for DA10 by scrutinizing the protein-protein interaction (PPI) networks using in silico tools.
Results
Among the genes that reside within the previously reported genomic coordinates (human chromosome assembly 38 or GRCh38 coordinates 2:179,700,000–188,500,000) of the causative agent of DA10, only TTN (the gene that codes for the protein Titin or TTN) follows the expression pattern similar to the other known DA associated genes and its expression is predominant in the skeletal and heart muscles. Titin also participates in biological pathways and processes relevant to arthrogryposes. TTN-related known skeletal muscle disorders follow the autosomal-dominant pattern of inheritance, which is a common characteristic of distal arthrogryposes as well.
Conclusion
Based on the findings of the analyses and their correlation with previous reports, TTN appears to be the candidate gene for DA10. Our attempt to discover a potential candidate gene may eventually lead to an understanding of disease mechanism and possible treatment strategies, as well as demonstrate the suitability of PPI in the search for candidate genes.
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Background
“Arthrogryposis” is derived from the Greek words “arthron”, meaning joint, and “gryposis” meaning curvature [1]. Arthrogryposis and arthrogryposis multiplex congenita (AMC) are used as generalized terms to describe inborn congenital contractures, which often affect multiple limbs [2]. These descriptive terms, however, do not denote any specific diagnosis for such conditions as AMCs have been recognized in different conditions [2, 3]. One child in every 3000 to 5100 live births is born with arthrogryposis with different levels of penetrance [1, 4]. Decreased in utero fetal movement is observed in every affected case, but the cause of such diminished movement can be vastly different [2]. In addition to maternal effects such as a bicornuate uterus, oligohydramnios, or intrauterine crowding (observed in twins) [5], mutations in certain genes contribute to AMC development [6].
Bamshad et al. described the most widely accepted clinical classification of AMC. According to this classification, AMC can be caused by amyoplasia, neurological abnormalities, or distal arthrogryposis. Amyoplasia is caused by impaired muscle growth leading to contractures that affect every symmetrical joint of the body. Internally rotated shoulders, extended elbows, flexed wrists, dislocated hips, equinovarus contractures in the feet, rigid fingers, and thumbs are common symptoms in these cases [5]. Many patients also have a mid-facial hemangioma. Most of these patients, however, have normal intelligence. Hereditary components have not been established for AMC caused by amyoplasia, and surgical intervention is usually needed for treatment [1]. Complications during central nervous system development and peripheral neuropathies can also lead to decreased fetal movement and arthrogryposis [5]. Occasionally, auto-antibodies from the mother can target fetal acetylcholine receptors and cause neuropathies in the fetus [1]. AMCs are inherited in an autosomal recessive manner, whereas the types and sub-types of distal arthrogryposes (DAs) are mostly autosomal dominant in nature [1, 4, 5, 7,8,9]. DA primarily affects the distal parts of the body, i.e., the hands and the legs. It is the second largest cause of AMC after amyoplasia [10]. According to the classification proposed by Bamshad et al [5], DA is characterized by multiple congenital contractures without a primary muscular or neurological disorder. DA patients are usually treated with the goal of improving the motor function of affected joints, strengthening muscles with physiotherapies, and correcting deformities through surgery [11].
Ten different types and several subtypes of DAs have been characterized and classified according to their proportion of shared features [5]. However, the genes associated with each type of DAs are yet to be categorized. DA10 is distinguished from the AMCs and other DAs by plantar flexion contractures, resulting in toe-walking during infancy [12, 13]. Additionally, patients show variability in contractures of the hip, hamstring, elbow, wrist, and finger joints [13]. Like the other DAs, DA10 is still poorly studied. In this study, we scrutinized the interactions among the already known arthrogryposis-associated gene products through protein-protein interaction (PPI) network analyses as well as database search and explored the potential candidate gene associated with the development of distal arthrogryposis type 10 (DA10).
Methods
Identification of the interactors of arthrogryposis-associated proteins
The list of genes that are known to be associated with different types and subtypes of DA (Table 1) was retrieved from the Online Mendelian Inheritance in Man® (OMIM®) database [6]. These genes were used as input in NetworkAnalyst 3.0 [ In this study, we scrutinized the protein-protein interaction (PPI) networks as well as the associated biological processes and pathways to identify the candidate gene for DA10. TTN resides within the previously reported genomic coordinates of the potential candidate gene of DA10. TTN is predominantly expressed in the skeletal and heart muscles and its expression follows a pattern similar to the other known DA-associated genes. TTN participates in biological pathways and processes relevant to arthrogryposis. Based on the findings of these in silico analyses and their correlation with previous reports, TTN appears to be the candidate gene for DA10.Conclusions
Availability of data and materials
All data generated or analyzed during this study are included in this published article (and its supplementary information files).
Abbreviations
- AMC:
-
Arthrogryposis multiplex congenita
- DA:
-
Distal arthrogryposis
- DA10:
-
Distal arthrogryposis type 10
- FDR:
-
False discovery rate
- PPI:
-
Protein-protein interaction
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Acknowledgements
This study was supported by a grant under special allocation in science and technology from the Ministry of Science and Technology, Bangladesh to AAS. The authors are thankful for the support.
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Ministry of Science and Technology, Bangladesh.
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AB: methodology, acquisition of data, and manuscript preparation. SDN: methodology, analysis of data, and manuscript preparation. TA: analysis and interpretation of data. MMH: interpretation and manuscript reviewing. SA: interpretation and manuscript reviewing. AAS: conceptualization, interpretation of data, and manuscript reviewing. The author(s) read and approved the final manuscript.
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Supplementary Information
Additional file 1: Supplementary Table 1.
List of interacting proteins in the network shown in Fig. 1.
Additional file 3: Supplementary Figure 1.
The DA associated genes (in red) that participate in hypertrophic cardiomyopathy, dilated cardiomyopathy and/or adrenergic signaling in cardiomyocytes pathways. The other nodes that participate in these pathways are shown in blue. The rest of the interacting proteins are shown in green.
Additional file 4: Supplementary Figure 2.
Tissue specific expression profiles of TTN and genes known to be associated with DAs [28].
Additional file 5: Supplementary Figure 3.
Tissue specific expression profiles of ITGA4, ITGAV, and NCKAP1 [28].
Additional file 6: Supplementary Figure 4.
Tissue specific expression profiles of FBXO2 [28].
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Biswas, A., Nath, S.D., Ahsan, T. et al. TTN as a candidate gene for distal arthrogryposis type 10 pathogenesis. J Genet Eng Biotechnol 20, 119 (2022). https://doi.org/10.1186/s43141-022-00405-5
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DOI: https://doi.org/10.1186/s43141-022-00405-5