The nuclear
lamins are important members of the intermediate filament (IF) family of
proteins, involved in structural support and regulation of the nuclear lamina. Different mutations in various members of these type V IF
proteins produce a staggering range of human disease phenotypes, which collectively have been termed "
laminopathies." Compelling examples are the wide range of inherited disorders that result from rare variants in LMNA encoding
lamin A/C. These
laminopathies include skeletal and cardiac muscle disorders, neuropathies, multisystem progeroid disorders, and
lipodystrophies, of which the latter are associated with several metabolic complications. Functions of
lamin A/C that have been shown to be compromised by distinct mutations in LMNA include loss of nuclear structural integrity, altered interaction with
transcription factors, and changes to post-translational processing of pre-
lamins. Recently, evidence has emerged that certain LMNA mutations, such as those causing partial
lipodystrophy, alter the interaction between
chromatin and
lamin A, in turn affecting the spatial orientation and distribution of
chromatin within the nucleus. Because
chromatin organization is exquisitely tied to global patterns of gene expression, the findings suggest a novel mechanism to explain the tissue-specific impact of a subset of
laminopathy-associated LMNA mutations.