ABSTRACT
Mutations in the de novo DNA methyltransferase DNMT3B lead to Immunodeficiency, Centromeric Instability and Facial anomalies (ICF) syndrome, type I. This syndrome is characterized, among other hypomethylated genomic loci, by severe subtelomeric hypomethylation that is associated with abnormally short telomere length. While it was demonstrated that the mean telomere length is significantly shorter in ICF type I cells, it is unknown whether all telomeres are equally vulnerable to shortening. To study this question we determined by combined telomere-FISH and spectral karyotyping the relative length of each individual telomere in lymphoblastoid cell lines (LCLs) generated from multiple ICF syndrome patients and control individuals. Here we confirm the short telomere lengths, and demonstrate that telomere length variance in the ICF patient group is much larger than in the control group, suggesting that not all telomeres shorten in a uniform manner. We identified a subgroup of telomeres whose relatively short lengths can distinguish with a high degree of certainty between a control and an ICF metaphase, proposing that in ICF syndrome cells, certain individual telomeres are consistently at greater risk to shorten than others. The majority of these telomeres display high sequence identity at the distal 2 kb of their subtelomeres, suggesting that the attenuation in DNMT3B methylation capacity affects individual telomeres to different degrees based, at least in part, on the adjacent subtelomeric sequence composition.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , Telomere/genetics , Abnormalities, Multiple/genetics , Cell Line , Centromere/genetics , Centromere/physiology , Chromosome Aberrations , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/genetics , Face/abnormalities , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Male , Mutation , Pedigree , Primary Immunodeficiency Diseases , Telomere/physiology , Telomere Shortening/genetics , DNA Methyltransferase 3BABSTRACT
Research has demonstrated that parents who smoke are often inadvertent sources of their children's first cigarettes. Teaching parents to restrict their tobacco may give pediatricians another method for helping parents who are not ready to quit smoking. This purpose of this study was to determine the feasibility of a program training pediatricians to discuss tobacco control with smoking parents and to examine changes in parents' tobacco control after the physician intervention. One month after the intervention by pediatricians, parents reported significantly improved tobacco control. They were more likely to count their packs and cigarettes and to keep their tobacco products at work and on their person. Parents reported restricting household control of adult smoking, and children were exposed to significantly less secondhand smoke. These results showed that it is possible to integrate advice about tobacco control into a busy pediatric practice and to improve parents' restrictions of their tobacco products.
