Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients
Abstract Background Hypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations an...
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| Format: | Article |
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BMC
2022-05-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-022-02334-5 |
| _version_ | 1818207889538416640 |
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| author | Defu Lin Huakang Du Sen Zhao Bowen Liu Hongcheng Song Guannan Wang Weiping Zhang Haiyan Liang Pei Liu Chao Liu Wenwen Han Zhenwu Li Yang Yang Shuofan Chen Lina Zhao Xiaoxin Li Zhihong Wu DISCO (Deciphering Disorders Involving Scoliosis & COmorbidities) study group Ning Sun Nan Wu |
| author_facet | Defu Lin Huakang Du Sen Zhao Bowen Liu Hongcheng Song Guannan Wang Weiping Zhang Haiyan Liang Pei Liu Chao Liu Wenwen Han Zhenwu Li Yang Yang Shuofan Chen Lina Zhao Xiaoxin Li Zhihong Wu DISCO (Deciphering Disorders Involving Scoliosis & COmorbidities) study group Ning Sun Nan Wu |
| author_sort | Defu Lin |
| collection | DOAJ |
| description | Abstract Background Hypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations and a cohort of 49 sporadic patients with hypospadias. Results A novel BRAF variant (NM_004333.6: c.362C > A) was found to co-segregate with the hypospadias phenotype in the disease pedigree. In cells overexpressing the BRAF mutant, the phosphorylation level of p38 MAPK was significantly increased as compared with the cells overexpressing the wild-type BRAF or RASopathy-related BRAF mutant. This variant further led to a reduced transcription level of the SRY gene, which is essential for the normal development of the male reproductive system. In the cohort of sporadic patients, we identified two additional variants in p38 MAPK signaling-related genes (TRIM67 and DAB2IP) potentially associated with hypospadias. Conclusion Our study expands the phenotypic spectrum of variants affecting p38 MAPK signaling toward the involvement of hypospadias. |
| first_indexed | 2024-12-12T04:36:06Z |
| format | Article |
| id | doaj.art-86f7eff09721442fa00d962aad5f197e |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-12T04:36:06Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-86f7eff09721442fa00d962aad5f197e2022-12-22T00:37:58ZengBMCOrphanet Journal of Rare Diseases1750-11722022-05-0117111010.1186/s13023-022-02334-5Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patientsDefu Lin0Huakang Du1Sen Zhao2Bowen Liu3Hongcheng Song4Guannan Wang5Weiping Zhang6Haiyan Liang7Pei Liu8Chao Liu9Wenwen Han10Zhenwu Li11Yang Yang12Shuofan Chen13Lina Zhao14Xiaoxin Li15Zhihong Wu16DISCO (Deciphering Disorders Involving Scoliosis & COmorbidities) study groupNing Sun17Nan Wu18Department of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesBeijing Key Laboratory for Genetic Research of Skeletal DeformityBeijing Key Laboratory for Genetic Research of Skeletal DeformityDepartment of Urology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesAbstract Background Hypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations and a cohort of 49 sporadic patients with hypospadias. Results A novel BRAF variant (NM_004333.6: c.362C > A) was found to co-segregate with the hypospadias phenotype in the disease pedigree. In cells overexpressing the BRAF mutant, the phosphorylation level of p38 MAPK was significantly increased as compared with the cells overexpressing the wild-type BRAF or RASopathy-related BRAF mutant. This variant further led to a reduced transcription level of the SRY gene, which is essential for the normal development of the male reproductive system. In the cohort of sporadic patients, we identified two additional variants in p38 MAPK signaling-related genes (TRIM67 and DAB2IP) potentially associated with hypospadias. Conclusion Our study expands the phenotypic spectrum of variants affecting p38 MAPK signaling toward the involvement of hypospadias.https://doi.org/10.1186/s13023-022-02334-5HypospadiasPedigreeProto-oncogene proteins B-raf (BRAF)Mitogen-activated protein kinases (MAPK)p38 mitogen-activated protein kinasesSex-determining region Y protein (SRY) |
| spellingShingle | Defu Lin Huakang Du Sen Zhao Bowen Liu Hongcheng Song Guannan Wang Weiping Zhang Haiyan Liang Pei Liu Chao Liu Wenwen Han Zhenwu Li Yang Yang Shuofan Chen Lina Zhao Xiaoxin Li Zhihong Wu DISCO (Deciphering Disorders Involving Scoliosis & COmorbidities) study group Ning Sun Nan Wu Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients Orphanet Journal of Rare Diseases Hypospadias Pedigree Proto-oncogene proteins B-raf (BRAF) Mitogen-activated protein kinases (MAPK) p38 mitogen-activated protein kinases Sex-determining region Y protein (SRY) |
| title | Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients |
| title_full | Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients |
| title_fullStr | Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients |
| title_full_unstemmed | Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients |
| title_short | Phenotype expansion of variants affecting p38 MAPK signaling in hypospadias patients |
| title_sort | phenotype expansion of variants affecting p38 mapk signaling in hypospadias patients |
| topic | Hypospadias Pedigree Proto-oncogene proteins B-raf (BRAF) Mitogen-activated protein kinases (MAPK) p38 mitogen-activated protein kinases Sex-determining region Y protein (SRY) |
| url | https://doi.org/10.1186/s13023-022-02334-5 |
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