Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome

Abstract

Silver-Russell syndrome (SRS, OMIM 180860) is a congenital disorder characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in approximately 10% of affected individuals. Given the crucial role of the 11p15 imprinted region in the control of fetal growth, we hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. We identified an epimutation (demethylation) in the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical SRS. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provide new insight into the pathogenesis of SRS and strongly suggest that the 11p15 imprinted region, in addition to those of 7p11.2-p13 and 7q31-qter, is involved in SRS.

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…Loss of methylation (LOM) at ICR1 accounts for over 50% of SRS cases, while gain of methylation (GOM) at ICR1 and LOM at ICR2 trigger BWS in approximately 10% and 60% of cases, respectively. In addition, maternal uniparental disomy of chromosome 7 (mUPD7) and paternal UPD of 11p15.5 are present in 7–10% of SRS and 20% of BWS, respectively [3–5]. …”

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

“…Proper establishment, and especially the subsequent somatic maintenance of these marks, is crucial, since their deregulation may lead to complex diseases in humans, and is frequently also observed in cancer. (18,19) Remarkably, three independent studies on Silver-Russell Syndrome (1)(2)(3) now report loss of DNA methylation at the H19 ICR, in about a third of patients. Silver-Russell Syndrome (SRS; OMIM 180860) is a congenital disorder characterised by intrauterine and postnatal growth retardation, facial dysmorphism and a series of minor features, including relative macrocephaly, skeletal asymmetry, early or precocious puberty, and genital abnormalities.…”

“…Overexpression of IGF2, due to different reasons, is one of the causes of the Beckwith-Wiedemann overgrowth syndrome (BWS) in humans. Now, three exciting studies pinpoint the imprinted IGF2 gene as being also involved in the Silver-Russell Syndrome (SRS) (1)(2)(3) a human syndrome that could be considered the opposite of BWS, since intrauterine and postnatal growth retardation are its main symptoms.…”

“…The novel studies now indicate that epigenetic modifications at the IGF2-H19 domain are causally involved in Silver-Russell Syndrome. (1)(2)(3) This raises interesting questions about possible other epigenetic mechanisms.…”

Asymétrie des génomes parentaux

“…En effet, la moitié des patients atteints du SRS présentent une perte de méthylation au niveau de l'ICR qui régule le domaine IGF2-H19 (Figure 2). Cette perte de méthylation mène à la perte d'expression d'IGF2 et, en conséquence, à un retard de croissance [29]. Il est intéressant de noter que chez les jumeaux homozygotes [30], qui sont issus d'un oeuf unique, il arrive que l'un des jumeaux soit atteint du syndrome SRS ou BWS, alors que l'autre est sain.…”