Nonsynonymous single nucleotide polymorphisms (nsSNPs) alter the encoded amino acid sequence, and are thus likely to affect the function of the proteins, and represent potential disease-modifiers. There is an enormous number of nsSNPs in the human population, and the major challenge lies in distinguishing the functionally significant and potentially disease-related ones from the rest. In this study, we analyzed the genetic variations that can alter the functions and the interactions of a group of cell cycle proteins (n = 60) and the proteins interacting with them (n = 26) using computational tools. As a result, we extracted 249 nsSNPs from 77 cell cycle proteins and their interaction partners from public SNP databases. Only 31 (12.4%) of the nsSNPs were validated. The majority (64.5%) of the validated SNPs were rare (minor allele frequencies < 5%). Evolutionary conservation analysis using the SIFT tool suggested that 16.1% of the validated nsSNPs may disrupt the protein function. In addition, 58% of the validated nsSNPs were located in functional protein domains/motifs, which together with the evolutionary conservation analysis enabled us to infer possible biological consequences of the nsSNPs in our set. Our study strongly suggests the presence of naturally occurring genetic variations in the cell cycle proteins that may affect their interactions and functions with possible roles in complex human diseases, such as cancer.

Identification of the disease-causing mutation in this family with long-term follow-up allows for earlier and more accurate identification of individuals at risk for this inherited progressive macular degeneration, provides for more accurate genetic counseling, and contributes to our understanding of the pathophysiology of this disorder.

The role of DNA repair in initiation, promotion, and progression of malignancy suggests that variations in DNA repair genes confer altered cancer risk. Accordingly, DNA repair gene variants have been studied extensively in the context of cancer predisposition. Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the human genome. A fraction of SNPs are located within the genes, which are likely to alter the gene expression and function. SNPs that change the encoded amino acid sequence of the proteins (non-synonymous; nsSNPs) are potentially genetic disease determinant variations. However, as not all amino acid substitutions are supposed to lead to a change in protein function, it will be necessary to have a priori prediction and determination of the functional consequences of amino acid substitutions per se, and then together with other genetic and environmental factors to study their possible association with a trait. Here we report the analysis of nsSNPs in 88 DNA repair genes and their functional evaluation based on the conservation of amino acids among the protein family members. Our analysis demonstrated that &gt;30% of variants of DNA repair proteins are highly likely to affect the function of the proteins drastically. In this study, we have shown that three nsSNPs, which were predicted to have functional consequences (XRCC1-R399Q, XRCC3-T241M, XRCC1-R280H), were already found to be associated with cancer risk. The strategy developed and applied in this study has the potential to identify functional protein variants of DNA repair pathway that may be associated with cancer predisposition.

A three-generation family with an autosomal dominant pattern dystrophy arising from a previously unreported splice site mutation in the RDS gene is described.