The roles of methylation of human imprinting genes in Russell–Silver syndrome (RSS)
Date Issued
2007
Date
2007
Author(s)
Lee, Mei-Hui
DOI
zh-TW
Abstract
Russell-Silver syndrome (RSS) is a rare genetic disorder characterized by growth delays before birth (intrauterine growth retardation; IUGR) and is associated with postnatal delayed speech, developmental delay and clinodactyly. Affected children exhibit unusual characteristic facial features and may have asymmetry or overgrowth of one side of the body. The aetiology of RSS is still unclear but it has been correlated with the degrees of gene methylation. To get more insights into the roles of gene methylation in RSS, we measure and analyze the degrees of methylations in a number of human imprinting genes for 27 patients with suspected RSS.
The level of DNA methylation is determined by Hpa II/ PstⅠPCR. We first examined the methylation levels of MEST, UBE3A, SNRPN, GRB10, H19, IGF2 and NESP55 for 17 normal controls in order to set up the normal reference ranges. The normal methylation indices (mean±2 SD) for the 7 genes mentioned above were estimated as 0.09±0.16, 0.11±0.18, 0.25±0.40, 0.59±0.26, 0.58±0.48, 0.77±0.36 and 0.82±0.24, respectively. Among the 27 RSS patients, there were 13 patients (48%) with aberrant methylation levels in GRB10 (9 hypermethylations and 4 hypomethylations), and 4 patients (15%), one patients (4%), 4 patients (15%), 4 patients (15%) with aberrant methylation levels in MEST, H19, IGF2 and NESP55, separately. All of the one patient aberrant in H19, 4 patients aberrant in IGF2,and 4 patients aberrant in NESP55 were hypomethylated, while all 4 patients aberrant in MEST were hypermethylated. In addition, all the 27 RSS patients had normal methylation levels in UBE3A. As a whole, there were 1 male patient with aberrant methylation levels in 4 genes, 6 patients (5 males and 1 female) with aberrant levels in 2 genes, 10 patients (7 males and 3 females) with aberrant levels in 1 genes and 10 patients (7 males and 3 females) without any aberration in all of the 6 genes (not inclusive of SNRPN).
The clinical findings complied with a very broad definition of RSS inclusive of IUGR, FTT (Failure to Thrive), typical face, asymmetry and clinodactyly. Notable additional findings include genital abnormalities, feeding difficulties, delayed speech, caf’e au lait spots, developmental delay and other anomaly. In 19 examined patients (not inclusive of the other 8 patients on account of unavailable clinical data), other anomaly were seen in 17 patients, FTT in 17, IUGR in 15, typical face in 14, asymmetry in 15, clinodactyly in 14, feeding difficulty in 9, developmental delay in 9, genital abnormality in 4, and delayed speech in 4. None of the patients had Café au lait spots.
Among the 6 patients (no. 2, 5, 8, 9, 16, 26) who have no abberant methylation in any examined genes but with clinical data, there are 67% (4/6) with IUGR, 83% (5/6) with FTT, 50% (3/6) with typical face, 100% (6/6) with Asymmetry, 80% (4/5) with clinodactyly, 100% (1/1) with feed difficulty, 0% (0/1) with delay speech, 100% (2/2) with developmental delay, and 100% (4/4) with other anomaly. This finding suggests that there are other genes involved in RSS. For example, patient no. 2 has 8 scores, but all the 6 genes are normal.
GRB10 known to interact with a number of receptor tyrosine kinases and signalling molecules belongs to a small family of adapter proteins in cytoplasma. GRB10 involves in signal transduction in developing embryos and regulates cell proliferation and apoptosis. Although 6 patients (exclude 3 patients without clinical syndrome data) with high methylation in GRB10 are all with IUGR, we can not jump to the conclusion that GRB10 is directly related to IUGR because there are patients with normal GRB10 who also have IUGR. Statistically, GRB10 hypermethylation are not related to FTT, TFA, ASY, CLIN, GAB, FDIF, DSP, CLA, DDE.
In sum, our study indicated that the level of methylation in GRB10 might be related to RSS, but current data still don’t have enough power to prove it. There should be other genes not studied in the current study that are involved in the etiology of RSS.
Subjects
羅素–西弗氏症
甲基化
GRB10基因
子宮內生長遲緩
身體不對稱
Russell-Silver syndrome
Methylation
GRB10
intrauterine growth retardation
asymmetry
Type
other
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