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Abstract
Fibrillin-1 (FBN1) is responsible for haploinsufficient and autosomal dominant Marfan syndrome. Even in the same Marfan pedigree, penetrance and expressivity in heterozygous individuals can differ and result in variable disease onset and severity. Thus, other factors in addition to mutations in FBN1 are likely to contribute to the disease. In this study, we examined the regulation of FBN1 in porcine Marfan syndrome model, focusing on DNA methylation patterns distinguishable as wild-type (WT) and FBN1 null (KO) alleles in heterozygous cells. Most importantly, the ratio of the transcriptionally active hypomethylated WT allele was altered during cellular passage and highly correlated with FBN1 mRNA level compared with that in the KO allele. Transcribed FBN1 RNA from the KO allele was abolished after splicing coupled with translational initiation, suggesting that the functional FBN1 mRNA levels were affected by DNA methylation of the WT allele.
Highlights
Fibrillin-1 (FBN1) is responsible for haploinsufficient and autosomal dominant Marfan syndrome
An FBN1 preRNA that contained exons and introns before splicing was clearly detected in the FBN1 homozygous KO cells and WT cells (Supplementary Fig. 1a), indicating that FBN1 is transcribed from both normal (WT) and FBN1-mutated null (KO) alleles, while the spliced and mature FBN1 mRNA detected by RT-PCR analysis was the transcript only from the WT allele
RNA from the KO allele apparently existed before splicing, whereas spliced mature KO mRNA became degraded by a nonsense-mediated RNA decay mechanism that recognizes the premature stop codon created by the 1-bp deletion within the FBN1 coding region of the KO allele
Summary
Fibrillin-1 (FBN1) is responsible for haploinsufficient and autosomal dominant Marfan syndrome. Our Marfan model pigs[7] exhibit haploinsufficiency with phenotypic variations in disease onset, mimicking the condition in humans, wherein differences in disease phenotypes or affected tissues have been reported even among patients from the same pedigree. Both types of FBN1 mutations are important for understanding the pathogenic mechanisms of Marfan syndrome, disease onset of our FBN1 KO cloned pig model was caused by haploinsufficiency This was confirmed by the absence of mutant mRNA with a premature stop codon[7]. The disease onset and severity of the Marfan model cloned pigs most likely result solely from a genetic mutation by a 1-bp deletion within the FBN1 coding region that causes a frameshift and creates a premature stop codon[7] and not from genomic sequence differences outside FBN1
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