Publikationsserver der RWTH Aachen University
Beitrag genetischer Varianten in den Genen LOT1(ZAC1/PLAGL1) und KCNQ1 zur Ätiologie des Silver-Russell-Syndroms
Abstract
dc:descriptionThe aim of this study was to identify relevant alterations in the genes LOT1(ZAC1/PLAGL1) and KCNQ1 which may play a role in the etiology of the Silver-Russell syndrome (SRS). For this reason, both genes were tested for genomic variations. Furthermore, a quantitative gene-copy analysis for LOT1(ZAC1/PLAGL1) was introduced to identify genomic imbalances. In addition, to characterize the quality of the detected alterations a control-cohort of humans with normal height was tested for these variants. No relevant pathogenic alterations in the gene LOT1(ZAC1/PLAGL1) which could be significant for SRS were observed in a group of 30 patients with SRS and 14 patients suffered from isolated intrauterine growth restriction (IUGR). Among the 30 SRS-patients, 15 carried hypomethylation in the ICR1 of the region 11p15.5. A mutation analysis revealed seven previously unknown genomic variants being identified as polymorphisms. Interestingly, the variants g.10212T>A and g.10214C>A in exon 3 showed a strong cohesion. In any case, further analysis of control persons of normal height unveiled that some of them also carried these variants, hence there is no influence on the growth of SRS patients suggested. Another variant, g.9567G>T, was only detected in one of the screened patients but not in unaffected individuals. A further implication for the SRS in this case is very unlikely because the patient inherited this variant of his mother. The maternal allele of LOT1(ZAC1/PLAGl1) is liable to genomic imprinting, thus the gene is only expressed by the paternal disposition. Therefore no influence on the disease may be expected of this variation. Moreover, a detected deletion in intron 5 also seems to be irrelevant for the expression of the LOT1-protein as it does not cause a frame shift. Thus, no control persons were screened for this variant. Possibly the deletion can induce a frame shift in the splice-variant ZAC1. This question remains unanswered because this investigation was not an aim of this study. All further revealed variants could also be detected among persons with normal height. Lastly, genomic imbalances could not be discovered so in conclusion a main contribution of LOT1(ZAC1/PLAGL1) for the SRS can be excluded. Ten SRS-patients without hypomethylation in the ICR1 were further screened for genomic variants in the gene KCNQ1. Four already known non-pathogenic polymorphisms could be detected. Unknown variations were not found, so mutations in the gene KCNQ1 as a cause for SRS could be ruled out for these patients. Because of the small sample size in this study a contribution of KCNQ1 to the etiology of SRS could not be utterly excluded. A leading role for this gene and its gene product is rather unlikely because it is not directly involved in growth processes. In conclusion, the results of this study elucidate that the imprinted genes LOT1(ZAC1/PLAGL1) and KCNQ1 do not play a major role in the etiology of SRS.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2010
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Jäger, Susanne
- Contributors dc:contributor
-
- Eggermann, Thomas
Subjects
dc:subject × 12Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger