{"id":58,"date":"2016-12-29T11:59:00","date_gmt":"2016-12-29T18:59:00","guid":{"rendered":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/?p=58"},"modified":"2017-01-07T11:11:16","modified_gmt":"2017-01-07T18:11:16","slug":"58","status":"publish","type":"post","link":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/2016\/12\/29\/58\/","title":{"rendered":"The KCNQ1OT1 imprinting control region and non-coding RNA."},"content":{"rendered":"<p>Chiesa et al. (2012). The KCNQ1OT1 imprinting control region and non-coding DNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases. <em>Hum Mol Genet.<\/em> 21(1): 10-25.<\/p>\n<p><strong>Introduction<\/strong><\/p>\n<ul>\n<li>Imprinting control regions (ICRs) are cis-acting regulatory elements of the imprinted loci<\/li>\n<li>Chromosome 11p15.5 has a large cluster of imprinted genes<\/li>\n<li>Divided into 2 separate domains that each have their own ICRs<\/li>\n<li>ICR1 is telomeric, ICR2 is centromeric, have different mechanisms of action<\/li>\n<li>ICR2 is the promoter of KCNQ1OT1 gene (non-coding, imprinted)\n<ul>\n<li><em>KCNQ1OT1<\/em> is antisense, contained within the protein-coding KCNQ1 gene<\/li>\n<li>Non-coding KCNQ1OT1 transcript silences imprinted genes of the centromeric domain on the paternal chromosome<\/li>\n<li>Methylation of ICR2 on maternal chromosome, not transcribed and imprinted genes are expressed<\/li>\n<\/ul>\n<\/li>\n<li>Changes in methylation patterns on the imprinting control regions (ICRs)<\/li>\n<li>Loss of methylation on the maternal allele of ICR2 results in BWS\n<ul>\n<li>Most common defect in BWS<\/li>\n<li>Leads to bi-allelic activation of <em>KCNQ1OT1 <\/em>and silencing of the imprinted genes<\/li>\n<li>This includes the cell growth inhibitor <em>CDKN1C<\/em><\/li>\n<\/ul>\n<\/li>\n<li>Inverse defects in DNA methylation at ICR1 causes BWS or SRS\n<ul>\n<li>With associated changes in the expression of <em>IGF2\/H19<\/em> transcripts<\/li>\n<\/ul>\n<\/li>\n<li>Mutation of the cell growth inhibitor CDKN1C (5% of BWS)<\/li>\n<li>Loss-of-function mutation in a <em>trans<\/em>-acting factor demonstrated in familial case of BWS<\/li>\n<li>Uniparental disomy frequently observed in BWS<\/li>\n<li>Chromosomal abnormalities \u2013 rarer, usually involve paternal duplications, maternal deletions or balanced maternal translocations in BWS\n<ul>\n<li>Maternal duplication usually observed in SRS<\/li>\n<\/ul>\n<\/li>\n<li>2 cases in this paper:\n<ul>\n<li>2 Mb long inverted duplication of entire imprinted gene cluster \u00e0 SRS phenotype<\/li>\n<li>160 kb duplication including ICR2 and 5\u2019 20 kb of KCNQ1OT1 co-segregating with BWS phenotype in 3 generations\n<ul>\n<li>Expression of truncated KCNQ1OT1 transcript, silencing of CDKN1C results<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><strong>Results<\/strong><\/p>\n<ol>\n<li><em>SRS family<\/em><\/li>\n<\/ol>\n<ul>\n<li>SRS patient born in family with no signs of SRS\n<ul>\n<li>Intra-uterine growth restriction, low birth weight and length<\/li>\n<li>Height and weight below the 3<sup>rd<\/sup> centile<\/li>\n<\/ul>\n<\/li>\n<li>Slight ICR1 hypomethyation, ICR2 hypermethylation observed in patient\n<ul>\n<li>Parents were both normal at both loci (50%)<\/li>\n<\/ul>\n<\/li>\n<li>Used microsatellite and SNP analysis to find de novo maternal duplication in the patient<\/li>\n<li>2 Mb duplication encompassing the entire imprinted gene cluster, only <em>in cis<\/em> (confirmed via FISH)<\/li>\n<li>Hypermethylation of CpGs throughout SRS patient 1, consistent with duplication of methylated maternal allele\n<ul>\n<li>Shows duplicated chromosome acquired imprinted methylation of ICR2<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<ol start=\"2\">\n<li><em>BWS family<\/em><\/li>\n<\/ol>\n<ul>\n<li>Female patient born to unrelated parents\n<ul>\n<li>Mother born with elevated birth weight, father normal<\/li>\n<li>Maternal uncle and aunt also had elevated birth weight<\/li>\n<li>Umbilical hernia also runs in the family on the maternal side<\/li>\n<\/ul>\n<\/li>\n<li>MS-MLPA \u2013 hypomethylation at ICR2 and normal methylation at ICR1 in III-6, II-4, II-3, I-4\n<ul>\n<li>Normal methylation in ICR2 and ICR2 at II-5, III-5<\/li>\n<li>Increased copy number of KCNQ1 exons 12-15 and ICR2 in all family members with hypomethylation<\/li>\n<li>Maternal transmission of 11p15.5 duplication from I-4 to II-3 and II-4, from II-4 to III-6<\/li>\n<\/ul>\n<\/li>\n<li>Identified <em>in cis<\/em> duplication of a portion of the<em> KCNQ1<\/em> gene (exon 12-15), ICR2 and most 5\u2019 20 kb of KCNQ1OT1\n<ul>\n<li>Excluded mutations of CDKN1C gene in patient 1 via exon sequencing<\/li>\n<\/ul>\n<\/li>\n<li>Extensive hypomethylation at ICR2 in all individuals with the 160 kb duplication\n<ul>\n<li>Loss of imprinted methylation of maternal allele evident in BWS patients 1 and 2<\/li>\n<li>160 kb duplication leads to imprinting alteration and BWS phenotype only with maternal transmission<\/li>\n<\/ul>\n<\/li>\n<li>By cloning the patient cells, determined that hypomethylation was likely due to lack of methylation of one of the two ICR2 copies present on the maternal chromosome<\/li>\n<li>Found KCNQ1OT1 gene expressed on the maternal chromosome\n<ul>\n<li>Bi-allelic expression of KCNQ1OT1 in duplication region but normal in non-duplicated region<\/li>\n<\/ul>\n<\/li>\n<li>Level of CDKN1C RNA was lower in BWS patient 2 vs. age-matched controls\n<ul>\n<li>Indicates silencing of CDKN1C by expressed KCNQ1OT1<\/li>\n<li>Confirmed that KCNQ1OT1 interacts with chromatin<\/li>\n<li>Interaction exerted at least partially by 5\u2019 20 kb sequence<\/li>\n<li>The silencing of CDKN1C likely occurs via interaction with chromatin<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Chiesa et al. (2012). The KCNQ1OT1 imprinting control region and non-coding DNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases. Hum Mol Genet. 21(1): 10-25. Introduction Imprinting control regions (ICRs) are cis-acting regulatory elements of the imprinted loci Chromosome 11p15.5 has a large cluster of imprinted genes Divided into 2 [&hellip;]<\/p>\n","protected":false},"author":8192,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1788162],"tags":[1788169,6812,1788168,1788170],"class_list":["post-58","post","type-post","status-publish","format-standard","hentry","category-paper-summaries","tag-clinical-studies","tag-genetics","tag-imprinting","tag-pedigrees"],"_links":{"self":[{"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/posts\/58","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/users\/8192"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/comments?post=58"}],"version-history":[{"count":4,"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/posts\/58\/revisions"}],"predecessor-version":[{"id":125,"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/posts\/58\/revisions\/125"}],"wp:attachment":[{"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/media?parent=58"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/categories?post=58"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.ubc.ca\/cdrohanbiol463\/wp-json\/wp\/v2\/tags?post=58"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}