There is still a NSC683864 molecular weight disproportion between the detailed description of HGPS phenotype and a poor understanding of its pathomechanism. Pathogenesis Significant progress in the understanding of progeria has been reached due to the detection, in patients, of a mutation in exon 11 of the LMNA gene. It is composed of 12 exons and encodes protein lamin A/C – a main component of the nuclear lamina. The most frequent mutation in HGPS is heterozygous single base substitution 1824 C > T in exon 11, which creates silent point mutation at codon 608 (G608G) and activates cryptic

splice site leading to truncated lamin A – progerin – lacking 50 amino acids on C-terminal end (13, 14) Also Inhibitors,research,lifescience,medical other LMNA mutations have been described e.g. 433 G > A (E145K), 1619 T > C (M540T), 1626 G > C (K542N), 1822 G > A (G608S), 1868 C > G (T623S), 1960 C > T (R654X) (9, 11, 13). At present, progeria is regarded as a member of the vast, and steadily

increasing group of laminopathies together with organ-specific syndromes: Emery-Dreifuss Inhibitors,research,lifescience,medical dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B, limb girdle dystrophy type 1B, partial familial lipodystrophy Dunnigan type (FPLD), and multisystem ones like mandibuloacral dysplasia (MAD) etc. The laminopathies are often overlapping, due to interaction of numerous nuclear proteins. Therefore, some cases of progeria can run a different course if overlapping with, for example, lipodystrophy, Emery-Dreifuss Inhibitors,research,lifescience,medical dystrophy or neuropathy. The overlapping cases may be atypical, some milder and associated with mutations Inhibitors,research,lifescience,medical in exons other than 11 e.g. 1, 2, 9, 10 exons. Progeria with atypical localization of LMNA mutation (i.e., different from 1824 C > T in exon 11) or with atypical phenotype (i.e., longer survival, absence of complete hair loss)

is sometimes described as “progeroid syndrome”. Kirshner et al. described a mild case of progeria associated with congenital myopathy (15). In this case, the point mutation 428 C > T was localized Inhibitors,research,lifescience,medical in exon 2. The same mutation and similar phenotype was described by Madej et al., in our Unit. In both cases, there was congenital myopathy, which could be due to overlapping with Emery-Dreifuss dystrophy. The Authors stressed the possibility of two phenotypes associated with one mutation (15). Electron microscopic study showed muscle cells with areas replaced by rod-shaped, trapezoidal, polygonal structures of Z-disc density and abnormal fibroblasts with Thymidine kinase aberrant nuclear architecture in extracellular space characterized by the lobulation of nuclear envelope. The fibroblast from progeria patients shows a rapid decline in proliferation towards the end of culture, with an increase in the fraction of apoptotic cells (16, 17). The severe phenotype of progeria may also be associated with mutation in gene ZMPSTE-24 – (FACE – 1) coding a zinc metalloproteinase involved in prelamin A post-translation processing to form mature lamin A (18, 19) (Fig. ​(Fig.2).2).