title: Phenomics and lamins: from disease to therapy.
abstract: Systematic correlation of phenotype with genotype is a key goal of the emerging field of phenomics, which is expected to help define complex diseases. Careful evaluation of phenotype-genotype associations in monogenic disorders, such as laminopathies, might provide new hypotheses to be tested with molecular and cellular studies and might also suggest potential new intervention strategies. For instance, evaluation of the clinical features of carriers of mutant LMNA in kindreds with familial partial lipodystrophy suggests rational, staged intervention using established pharmaceutical agents to prevent cardiovascular complications not just for patients with lipodystrophy but by extension for patients with the common metabolic syndrome. Careful non-invasive imaging shows phenotypic differences between partial lipodystrophy due to mutant LMNA and not due to mutant LMNA. Furthermore, hierarchical cluster analysis detects systematic relationships between organ involvement in laminopathies and mutation position in the LMNA genomic sequence. However, sometimes the same LMNA mutation can underlie markedly different clinical phenotypes; cellular and molecular experiments can help to explain the mechanistic basis for such differences. Finally, promising novel treatment modalities for laminopathies, such as farnesyl transferase inhibition and gene-based therapies, might help not only to illuminate mechanisms that link genotype to phenotype, but also to provide hope for patients suffering with laminopathies, since these treatments are designed to modulate key early or proximal steps in the pathogenesis of these disorders.
authors.affiliation: Schulich School of Medicine and Dentistry, University of Western Ontario and Vascular Biology Research Group, Robarts Research Institute, London, Ontario, Canada N6A 5K8. hegele@robarts.ca
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D004252:DNA Mutational Analysis / Q000379:methods / Q000639:trends; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015316:Genetic Therapy / Q000639:trends; D023281:Genomics / Q000379:methods / Q000639:trends; D005838:Genotype; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008060:Lipodystrophy / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: D034904:Lamin Type A