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'.

Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations

“…Hegele using hierarchical cluster analysis for assembling laminopathies according to phenotypic similarity found that LMNA mutations at the 5 0 of codon 416 were seen more frequently in laminopathies with cardiac or neurological involvement, and in addition several overlapping syndromes, while mutations at the 3 0 of codon 423 are more likely to be associated with simple partial lipodystrophy, progeria syndrome, or mandibuloacral dysplasia (34). Our findings are in agreement with this, as the mutations found at the 3 0 to the nuclear localization signal were in patients with simple partial lipodystrophy.…”

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

“…Cases with haploinsufficiency or homozygous mutations have also been reported [4,6]. A hierarchical cluster analysis revealed interesting genotype/phenotype correlations [13]. There was a trend for mutations in the alpha-helical regions to cause muscular dystrophy, while mutations in globular regions were more likely to have been responsible for lipodystrophies.…”

Familial partial lipodystrophy (Dunnigan syndrome) due to LMNA gene mutation: The first description of its clinical case in Russia

“…FPLD2 является одной из 16 различных нозологических форм ламинопатий (так называемых аллельных серий) [5], раз-вивающихся в результате более 100 различных мутаций в гене LMNA, из них 12 заболеваний наследуются по аутосомно-доми-нантному типу, а 4 остальных -по аутосомно-рецессивному [6]. При этом расположение мутации в первичной генетической по-следовательности ДНК LMNA влияет на выраженность и харак-тер патологических изменений.…”