LMNA mutation position predicts organ system involvement in laminopathies

Abstract

The underlying disease mechanisms likely include mutation effects on the nuclear envelope and on interactions between lamins and transcription factors. At the same time, can a simple genomic attribute -- for instance, mutation position within the LMNA sequence -- predict the complex phenotypic effects? In order to assess this, hierarchical cluster analysis (HCA) was used for assembling 16 laminopathies into two classes based on organ system involvement. Ninety-one reported causative LMNA mutations in these laminopathies were then classified according to their position upstream or downstream of the nuclear localization signal sequence (NLS). Contingency analysis was used in order to assess a non-random relationship between HCA laminopathy class and LMNA mutation position relative to the NLS. HCA laminopathy class and LMNA mutation position were strongly associated (p < 0.0001). The odds ratio for general association between an HCA class 1 laminopathy and a mutation upstream of the NLS sequence was 8.4 (95% confidence interval = 2.9 - 24.7, p < 0.0001). Although the underlying molecular biology is complex, the findings support the hypothesis that laminopathy phenotype and LMNA genotype are non-randomly associated. Furthermore, HCA may be a tool to help with the study of phenotype - genotype associations, or 'phenomics'.