Berrant Splicing Of Lamin A

A well known example is a mutation in lmna which introduces a novel 5 splice site and generates a truncated lamin a protein that impairs nuclear membrane function.

Berrant splicing of lamin a. The alternatively spliced products of lmna lamin c and prelamin a the precursor to lamin a are produced in similar amounts in most tissues and have largely redundant functions this redundancy suggests that diseases such as hutchinson gilford progeria syndrome hgps that are caused by prelamin a specific mutations could be treated by shifting the output of lmna more toward lamin c. On the other hand the two b type lamins b1. The lmna gene gives rise to at least three isoforms lamin a c lamin aδ10 as a result of normal alternative splicing regulated by cis and trans acting regulatory factors as well as the 5 and 3 untranslated regions of the gene. The two main isoforms lamin a and c are constitutive components of the fibrous nuclear lamina and have diverse physiological roles ranging from.

Carboni n 1 floris m mateddu a porcu m marrosu g solla e cocco e mura m marini s maioli ma piras r aste r marrosu mg. Another example is aberrant splicing of sall1 which produces an isoform with a premature termination codon ptc. The lmna gene gives rise to at least three isoforms lamin a c lamin aδ10 as a result of normal alternative splicing regulated by cis and trans acting regulatory factors as well as the 5 and 3 untranslated regions of the gene. 1a lamin a and lamin c are major components of the nuclear lamina a complex molecular interface located between the inner membrane of the nuclear envelope and chromatin lamins a and c are also distributed throughout the nucleoplasm.

The occurrence of lamin a aberrant splicing in wild type cells suggests that δ50 lamin a is present in cells from healthy individuals. Aberrant splicing in the lmna gene caused by a novel mutation on the polypyrimidine tract of intron 5. Due to alternative splicing the lamin a gene generates several isoforms including lamin a c c2 and lamin ad10 cau et al. To identify small molecule modulators of aberrant lmna splicing a homogenous assay was constructed in hela cells that used a gfp containing minigene to report on correction of aberrant splicing in lamin a and a rfp dsred2 to report on cell viability uniformity and nonspecific effects on the assay signal.

A truncated protein of the expected molecular weight was detected in wild type cells by antibodies against lamin a and c lamin a c upon extraction of soluble proteins and enrichment for membrane associated. This leads to global gene expression changes and premature aging.