Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation
Skeletal development throughout the embryonic and postnatal phases is a dynamic process, based on bone remodeling and the balance between the activities of osteoclasts and osteoblasts modulating skeletal homeostasis. The Notch signaling pathway is a regulator of several developmental processes, and...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00534/full |
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| author | Tlili Barhoumi Tlili Barhoumi Marwan Nashabat Marwan Nashabat Bandar Alghanem Bandar Alghanem AlShaimaa Alhallaj AlShaimaa Alhallaj Mohamed Boudjelal Mohamed Boudjelal Muhammad Umair Saud Alarifi Ahmed Alfares Saad A. Al Mohrij Majid Alfadhel Majid Alfadhel Majid Alfadhel |
| author_facet | Tlili Barhoumi Tlili Barhoumi Marwan Nashabat Marwan Nashabat Bandar Alghanem Bandar Alghanem AlShaimaa Alhallaj AlShaimaa Alhallaj Mohamed Boudjelal Mohamed Boudjelal Muhammad Umair Saud Alarifi Ahmed Alfares Saad A. Al Mohrij Majid Alfadhel Majid Alfadhel Majid Alfadhel |
| author_sort | Tlili Barhoumi |
| collection | DOAJ |
| description | Skeletal development throughout the embryonic and postnatal phases is a dynamic process, based on bone remodeling and the balance between the activities of osteoclasts and osteoblasts modulating skeletal homeostasis. The Notch signaling pathway is a regulator of several developmental processes, and plays a crucial role in the development of the human skeleton by regulating the proliferation and differentiation of skeletal cells. The Delta Like-1 (DLL1) gene plays an important role in Notch signaling. We propose that an identified alteration in DLL1 protein may affect the downstream signaling. In this article, we present for the first time two siblings with a mutation in the DLL1 gene, presenting with congenital vertebral malformation. Using variable in silico prediction tools, it was predicted that the variant was responsible for the development of disease. Quantitative reverse-transcription polymerase chain reaction (PCR) for the Notch signaling pathway, using samples obtained from patients, showed a significant alteration in the expression of various related genes. Specifically, the expression of neurogenic locus notch homolog protein 1, SNW domain-containing protein 1, disintegrin, and metalloproteinase domain-containing proteins 10 and 17, was upregulated. In contrast, the expression of HEY1, HEY2, adenosine deaminase (ADA), and mastermind-like-1 (MAML-1) was downregulated. Furthermore, in a phosphokinase array, four kinases were significantly changed in patients, namely, p27, JANK1/2/3, mitogen- and stress-activated protein kinases 1 and 2, and focal adhesion kinase. Our results suggest an implication of a DLL1 defect related to the Notch signaling pathway, at least in part, in the morphologic abnormality observed in these patients. A limitation of our study was the low number of patients and samples. Further studies in this area are warranted to decipher the link between a DLL1 defect and skeletal abnormality. |
| first_indexed | 2024-04-13T02:08:53Z |
| format | Article |
| id | doaj.art-0180ef22e54641269c552260ad305dc4 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-13T02:08:53Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-0180ef22e54641269c552260ad305dc42022-12-22T03:07:21ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-06-011010.3389/fgene.2019.00534458048Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral MalformationTlili Barhoumi0Tlili Barhoumi1Marwan Nashabat2Marwan Nashabat3Bandar Alghanem4Bandar Alghanem5AlShaimaa Alhallaj6AlShaimaa Alhallaj7Mohamed Boudjelal8Mohamed Boudjelal9Muhammad Umair10Saud Alarifi11Ahmed Alfares12Saad A. Al Mohrij13Majid Alfadhel14Majid Alfadhel15Majid Alfadhel16King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaKing Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaDivision of Genetics, Department of Pediatrics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaKing Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaKing Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaKing Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaMedical Genomics Research Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaDepartment of Zoology, College of Science, King Saud University, Riyadh, Saudi ArabiaDepartment of Pediatrics, College of Medicine, Qassim University, Buraidah, Saudi ArabiaDepartment of Surgery, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaKing Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaDivision of Genetics, Department of Pediatrics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaMedical Genomics Research Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaSkeletal development throughout the embryonic and postnatal phases is a dynamic process, based on bone remodeling and the balance between the activities of osteoclasts and osteoblasts modulating skeletal homeostasis. The Notch signaling pathway is a regulator of several developmental processes, and plays a crucial role in the development of the human skeleton by regulating the proliferation and differentiation of skeletal cells. The Delta Like-1 (DLL1) gene plays an important role in Notch signaling. We propose that an identified alteration in DLL1 protein may affect the downstream signaling. In this article, we present for the first time two siblings with a mutation in the DLL1 gene, presenting with congenital vertebral malformation. Using variable in silico prediction tools, it was predicted that the variant was responsible for the development of disease. Quantitative reverse-transcription polymerase chain reaction (PCR) for the Notch signaling pathway, using samples obtained from patients, showed a significant alteration in the expression of various related genes. Specifically, the expression of neurogenic locus notch homolog protein 1, SNW domain-containing protein 1, disintegrin, and metalloproteinase domain-containing proteins 10 and 17, was upregulated. In contrast, the expression of HEY1, HEY2, adenosine deaminase (ADA), and mastermind-like-1 (MAML-1) was downregulated. Furthermore, in a phosphokinase array, four kinases were significantly changed in patients, namely, p27, JANK1/2/3, mitogen- and stress-activated protein kinases 1 and 2, and focal adhesion kinase. Our results suggest an implication of a DLL1 defect related to the Notch signaling pathway, at least in part, in the morphologic abnormality observed in these patients. A limitation of our study was the low number of patients and samples. Further studies in this area are warranted to decipher the link between a DLL1 defect and skeletal abnormality.https://www.frontiersin.org/article/10.3389/fgene.2019.00534/fullbone developmentcongenital vertebral malformationDelta Like-1Notch signaling pathwayscoliosis |
| spellingShingle | Tlili Barhoumi Tlili Barhoumi Marwan Nashabat Marwan Nashabat Bandar Alghanem Bandar Alghanem AlShaimaa Alhallaj AlShaimaa Alhallaj Mohamed Boudjelal Mohamed Boudjelal Muhammad Umair Saud Alarifi Ahmed Alfares Saad A. Al Mohrij Majid Alfadhel Majid Alfadhel Majid Alfadhel Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation Frontiers in Genetics bone development congenital vertebral malformation Delta Like-1 Notch signaling pathway scoliosis |
| title | Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation |
| title_full | Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation |
| title_fullStr | Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation |
| title_full_unstemmed | Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation |
| title_short | Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation |
| title_sort | delta like 1 gene mutation a novel cause of congenital vertebral malformation |
| topic | bone development congenital vertebral malformation Delta Like-1 Notch signaling pathway scoliosis |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.00534/full |
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