A Novel Synonymous Variant in the AVP Gene Associated with Autosomal Dominant Familial Neurohypophyseal Diabetes Insipidus Causes Partial RNA Missplicing
| Autor: | Søren Rittig, Jan-Ove Johansson, Jane H. Christensen, Charlotte Siggaard Rittig, Niels Gregersen, Thomas J. Corydon, Helene Kvistgaard |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Endocrine and Autonomic Systems Endocrinology Diabetes and Metabolism Prohormone Intron Biology medicine.disease 03 medical and health sciences Cellular and Molecular Neuroscience Exon 030104 developmental biology Endocrinology Internal medicine Diabetes insipidus medicine Coding region Allele Gene hormones hormone substitutes and hormone antagonists medicine.drug Minigene |
| Zdroj: | Neuroendocrinology. 107:167-180 |
| ISSN: | 1423-0194 0028-3835 |
| Popis: | Objective: Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is characterized by severe polyuria and polydipsia and is caused by variations in the gene encoding the AVP prohormone. This study aimed to ascertain a correct diagnosis, to identify the underlying genetic cause of adFNDI in a Swedish family, and to test the hypothesis that the identified synonymous exonic variant in the AVP gene (c.324G>A) causes missplicing and endoplasmic reticulum (ER) retention of the prohormone. Design/Patients: Three affected family members were admitted for fluid deprivation test and dDAVP (1-deamino-8-d-arginine-vasopressin) challenge test. Direct sequencing of the AVP gene was performed in the affected subjects, and genotyping of the identified variant was performed in family members. The variant was examined by expression of AVP minigenes containing the entire coding regions as well as intron 2 of AVP. Methods/Results: Clinical tests revealed significant phenotypical variation with both complete and partial adFNDI phenotype. DNA analysis revealed a synonymous c.324G>A substitution in one allele of the AVP gene in affected family members only. Cellular studies revealed both normally spliced and misspliced pre-mRNA in cells transfected with the AVP c.324G>A minigene. Confocal laser scanning microscopy showed collective localization of the variant prohormone to ER and vesicular structures at the tip of cellular processes. Conclusion: We identified a synonymous variant affecting the second nucleotide of exon 3 in the AVP gene (c.324G>A) in a family in which adFNDI segregates. Notably, we showed that this variant causes partial missplicing of pre-mRNA, resulting in accumulation of the variant prohormone in ER. Our study suggests that even a small amount of aberrant mRNA might be sufficient to disturb cellular function, resulting in adFNDI. |
| Databáze: | OpenAIRE |
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