Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics.

Synonymous (also known as silent) variations are by definition not considered to change the coded protein. Still many variations in this category affect either protein abundance or properties. As this situation is confusing, we have recently introduced systematics for synonymous variations and those that may on the surface look like synonymous, but these may affect the coded protein in various ways. A new category, unsense variation, was introduced to describe variants that do not introduce a stop codon into the variation site, but which lead to different types of changes in the coded protein. Many of these variations lead to mRNA degradation and missing protein. Here, consequences of the systematics are discussed from the perspectives of variation annotation and interpretation, evolutionary calculations, nonsynonymous-to-synonymous substitution rates, phylogenetics and other evolutionary inferences that are based on the principle of (nearly) neutral synonymous variations. It may be necessary to reassess published results. Further, databases for synonymous variations and prediction methods for such variations should consider unsense variations. Thus, there is a need to evaluate and reflect principles of numerous aspects in genetics, ranging from variation naming and classification to evolutionary calculations.

A Novel Synonymous Variant in the AVP Gene Associated with Autosomal Dominant Familial Neurohypophyseal Diabetes Insipidus Causes Partial RNA Missplicing.

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.