Molecular (Epi)Genetics Lab Research Unit, Hospital Txagorritxu, E-01009, Vitoria-Gasteiz, Alava, Spain.
J Clin Endocrinol Metab. 2012 Jun;97(6):E1060-7. doi: 10.1210/jc.2012-1081. Epub 2012 Apr 4.
Genomic imprinting is the modification of the genome so that genes from only one (rather than two) of the parental alleles are expressed. The mechanism underlying imprinting is epigenetic, occurring via changes in DNA methylation and histone modifications rather than through alterations in the DNA sequence. To date, nine different imprinting disorders have been clinically and genetically identified and a considerable research effort has been focused on determining the cause of the corresponding methylation defects.
Our objective was to identify multilocus imprinting defects and characterize any mutations in trans-acting genes in patients with pseudohypoparathyroidism (PHP) caused by epigenetic alterations at GNAS locus.
We have investigated multilocus imprinting defects in 22 PHP patients with aberrant methylation at the GNAS locus not due to previously described deletions or to paternal uniparental disomy (UPD) of chromosome 20.
We found that, in contrast to what has been described in growth disorders, multilocus hypomethylation is an uncommon event in PHP patients. We were also unable to identify any genetic alteration causative of the epigenetic defects in the currently known methylation regulatory genes.
Our work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS.
基因组印记是对基因组的修饰，使得来自父母双方的等位基因只有一方（而不是两方）得到表达。印记的机制是表观遗传的，通过 DNA 甲基化和组蛋白修饰的变化发生，而不是通过 DNA 序列的改变。迄今为止，已经临床和遗传鉴定了九种不同的印记疾病，并且已经进行了相当大的研究努力来确定相应的甲基化缺陷的原因。
我们的目的是确定多基因印记缺陷，并在由 GNAS 位点表观遗传改变引起的假性甲状旁腺功能减退症（PHP）患者中，研究跨基因印迹缺陷，并表征任何反式作用基因的突变。
我们研究了 22 名 PHP 患者的多基因印记缺陷，这些患者在 GNAS 位点的甲基化异常，但不是由于先前描述的缺失或 20 号染色体的父系单亲二体性（UPD）引起的。
我们发现，与生长障碍中描述的情况相反，多基因低甲基化在 PHP 患者中是一种罕见的事件。我们也无法确定在目前已知的甲基化调节基因中任何遗传改变是导致表观遗传缺陷的原因。
我们的工作表明，如果存在调节 GNAS 位点印迹建立或维持的反式作用基因，它应该是由 GNAS 位点表观遗传缺陷引起的 PHP 病例所特有的。
