Six missense mutations are predicted to occur within the head-to- tail selleck inhibitor interaction

region as defined by Strelkov (P4R, T101, R28W, E33D, E358K, R386T). Figure 1 also summarizes the clinical selleck bio phenotypes of the overlapping syndromes associated to the reported LMNA A/C gene missense mutations, related to lamin structure and its main partners. Table 1. Characteristics of complex phenotypes caused by dominant LMNA gene mutations and of the related genetic alterations. Table 2. Distribution and frequency of the mutations causing the complex phenotypes distributed per exon. Figure 1. Causative missense mutations in the context of the lamin A/C protein organization and related overlapping Inhibitors,research,lifescience,medical syndromes. Discussion Inhibitors,research,lifescience,medical We report a meta-analysis describing the clinical features of all overlapping syndromes related to dominant LMNA gene mutations so far published and the possible relationship with the underlying genetic alterations. We identified at least 14 different overlapping syndromes due to dominant mutations on the Lamin A/C gene. As shown in tables 1 and ​and2,2, LMNA gene mutations may be associated to complex phenotypes obtained by the variable association

of different phenotypes Inhibitors,research,lifescience,medical including metabolism disturbances, premature ageing syndromes, dermatologic changes, skeletal and cardiac compromise, nervous system alterations. The most frequent overlapping syndrome linked to LMNA gene alterations

is the association between metabolic alterations and skeletal and/or cardiac involvement caused by inframe mutations spread Inhibitors,research,lifescience,medical throughout the gene. It is likely that the pathogenic mechanism underlying this condition is the poison peptide effect: as a matter of fact, all the mutations so far identified alter the biochemical properties of A type lamins, either perturbing their stability or modifying the possible Inhibitors,research,lifescience,medical interactions with the numerous binding partners (54). The overlapping syndrome characterized by the association of skeletal and/or cardiac compromise with neuropathy and inconstant dermatologic abnormalities are caused by mutations spread throughout the gene; a possible pathogenic effect should be either a dominant negative or even a haploinsufficiency secondary to the production of un unstable mRNA or of a mutated protein, lacking the typical structure of intermediate filaments. Brefeldin_A For the third and fourth group of complex phenotypes, obtained by the variable association among muscle and/or heart disease, peripheral neuropathy, metabolism disturbances and concomitant presence of lipodystrophy, the few reports so far published do not consent any final correlation. However, the presence of either missense or silent mutations suggest that a dominant negative effect may play a major role in the pathogenesis of these two entities.