Ashraf Yahia1,2,3, Zhefan Stephen Chen4, Ammar E Ahmed5, Sara Emad6, Rawaa Adil6, Rayan Abubaker7, Shaimaa Omer M A Taha8, Mustafa A Salih9, Liena Elsayed10, Ho Yin Edwin Chan4,11, Giovanni Stevanin3,12. 1. Department of Biochemistry, Faculty of Medicine, University of Khartoum, Alqsr Street, Khartoum, Sudan. 2. Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan. 3. Institut du Cerveau, INSERM U1127, CNRS UMR7225, Sorbonne Université, Paris, France. 4. School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, SAR, China. 5. Department of Physiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. 6. Faculty of Medicine, University of Khartoum, Khartoum, Sudan. 7. Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan. 8. Department of Radiology, Dar Al Elaj Specialized Hospital, Khartoum, Sudan. 9. Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 10. Department of Biochemistry, Faculty of Medicine, University of Khartoum, Alqsr Street, Khartoum, Sudan. doctorlbo@hotmail.com. 11. Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, SAR, China. 12. Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France.
Abstract
BACKGROUND: CCDC88C is a ubiquitously expressed protein with multiple functions, including roles in cell polarity and the development of dendrites in the nervous system. Bi-allelic mutations in the CCDC88C gene cause autosomal recessive congenital hydrocephalus (OMIM #236600). Studies recently linked heterozygous mutations in CCDC88C to the development of the late-onset spinocerebellar ataxia type 40 (OMIM #616053). CASE PRESENTATION: A 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. Exome sequencing, in-silico analysis, and Sanger sequencing identified the heterozygous NM_001080414.4:c.1993G > A (p.E665K) variant in CCDC88C as a potential cause of her illness. To explore the pathogenicity of the NM_001080414.4:c.1993G > A (p.E665K) variant, we expressed it in human embryonic kidney 293 cells and assessed its effects on apoptosis. In our experiment, NM_001080414.4:c.1993G > A (p.E665K) induced JNK hyper-phosphorylation and enhanced apoptosis. In contrast to previous reports, our patient developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. CONCLUSION: We, herein, heighlighted the possibility of extending the phenotype associated with variants in CCDC88C to include early-onset pure hereditary spastic paraplegia.
BACKGROUND:CCDC88C is a ubiquitously expressed protein with multiple functions, including roles in cell polarity and the development of dendrites in the nervous system. Bi-allelic mutations in the CCDC88C gene cause autosomal recessive congenital hydrocephalus (OMIM #236600). Studies recently linked heterozygous mutations in CCDC88C to the development of the late-onset spinocerebellar ataxia type 40 (OMIM #616053). CASE PRESENTATION: A 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. Exome sequencing, in-silico analysis, and Sanger sequencing identified the heterozygous NM_001080414.4:c.1993G > A (p.E665K) variant in CCDC88C as a potential cause of her illness. To explore the pathogenicity of the NM_001080414.4:c.1993G > A (p.E665K) variant, we expressed it in humanembryonic kidney 293 cells and assessed its effects on apoptosis. In our experiment, NM_001080414.4:c.1993G > A (p.E665K) induced JNK hyper-phosphorylation and enhanced apoptosis. In contrast to previous reports, our patient developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. CONCLUSION: We, herein, heighlighted the possibility of extending the phenotype associated with variants in CCDC88C to include early-onset pure hereditary spastic paraplegia.
Entities:
Keywords:
CCDC88C; Hereditary spastic paraplegia; Spinocerebellar ataxia type 40; Sudan
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