Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin–Lowry syndrome

Abstract

Two novel mutations of the ribosomal S6 kinase 2 gene (also known as RSK2) have been identified in two unrelated patients with Coffin-Lowry syndrome. The first mutation consists of a de novo insertion of a 5'-truncated LINE-1 element at position -8 of intron 3, which leads to a skipping of exon 4, leading to a shift of the reading frame and a premature stop codon. The L1 fragment (2800 bp) showed a rearrangement with a small deletion, a partial inversion of the ORF 2, flanked by short direct repeats which duplicate the acceptor splice site. However, cDNA analysis of the patient shows that both sites are apparently not functional. The second family showed the nucleotide change 803T>C in exon 10, resulting in the F268S mutation. This mutation was detected in two monozygotic twin patients and in their mother, who was mildly affected. The patients fulfill the clinical criteria of the syndrome, and therefore the mutation provides further support for the importance of phenylalanine at position 268, which is highly conserved in the protein kinase domain of many serine-threonine protein kinases.

Epigenetics in the pathogenesis of rheumatoid arthritis

“…DNA hypermethylation-mediated silencing of DNA repair genes (for example, MGMT and MLH1 ) can result in inactivation of cellular mechanisms responsible for keeping the genetic mutation rate low [34,35] or in induction of microsatellite instability as described in certain types of cancer [36,37]. DNA hypomethylation can reactivate retrotransposons (for example, long and short interspersed nuclear elements), which then promote genetic mutations by inserting extra nucleotides into the exons or regulatory regions of genes [38,39]. …”

Long interspersed nuclear elements (LINEs) show tissue-specific, mosaic genome and methylation-unrestricted, widespread expression of noncoding RNAs in somatic tissues of the rat

“…We also observed tissue-specific methylation patterns of P1-LINE with respect to the hypermethylated 5kb Msp I band in the lungs and thymus and the hypomethylated 2.8, 1.3, 0.89 and 0.4 kb well as in other diseases such as hemophilia, Duchenne Muscular Dystrophy (DMD), β-thalassemia, chronic granulomatous disease (CGD) and Coffin-Lowry Syndrome (CLS). [59][60][61][62][63][64][65][66][67][68][69][70][71] Therefore, expression of L1s is generally correlated with genome rearrangement, genomic instability, alterations in gene expression and diseases. 72 Recently, LINEs have been reviewed as a major source of genetic disposition to diseases in humans.…”

Identification of Cryptic Novel α-Galactosidase A Gene Mutations: Abnormal mRNA Splicing and Large Deletions

“…This overlapped 15 nucleotide element is known as a target site duplication (TSD) sequence. An exonic/intronic L1 insertion mutation has also been found in some other genetic diseases (Awano et al 2010;Kagawa et al 2014), immunity disorders (Brouha et al 2002), cancers (Wimmer et al 2011), and neurologic diseases (Martínez-Garay et al 2003). The L1 retrotransposon leads to splicing out of the exon 4 element in pre-mRNA maturation.…”