Untersuchungen zur Rolle genetischer Veränderungen in der chromosomalen Region 11p15 bei der Entstehung des Silver-Russell-Syndroms

Silver-Russell-Syndrome (SRS) is a clinically heterogeneous syndrome, associated with pre- and postnatal growth retardation, cranial dysmorphisms, clinodactyly of the fifth finger, skeletal asymmetry and relative macrocephaly. The syndrome usually occurs sporadically, but in some cases a familial accumulation can be observed. 10% of the SRS-Patients show a maternal uniparental dysomie (UPD) of chromosome 10. Therefore different growth-regulating genes on chromosome 7 have been analysed. So far, however, no responsible gene could be determined. Kosaki et al. (2000) and Fisher et al. (2002) reported four patients with growth retardation and SRS-like features, which had a duplication of the maternal chromosomal region 11p15.5. Interestingly a paternal duplication of this region leads to the Beckwith-Wiedemann-syndrome (BWS), which is associated with overgrowth. Therefore it is possible that a duplication of the region 11p15.5 leads to growth retardation or overgrowth, due to decreased or increased expression of imprinted growth-regulating genes. Furthermore, some patients with BWS showed a paternal UPD 11 as well as changed imprinting patterns and mutations in the IGF2 and CDKN1C genes, which lie in the region 11p15.5. Owing to the discoveries of Kosaki et al. (2000) and Fisher et al. (2002) as well as the findings in BWS it is possible that a maternal duplication of the region 11p15.5, a maternal UPD11 as well as changed imprinting patterns and mutations in the growth regulating genes IGF2 and CDKN1C participate in the aetiology of SRS. In this thesis 46 Patients with SRS and their families were screened for maternal UPD11 and duplications of the region 11p15.5. Furthermore 40 patients were screened for mutations in the growth-regulating genes IGF2 and CDKN1C. The occurrence of variants in the IGF2-gene, which were previously associated with the body-mass-index (Gaunt et al. 2001) were compared to a collective of controls. Additionally, changes in the imprinting patterns of the IGF2 gene have been described in connection with BWS (Algar et al. 2002), so that variances in the methylation of the IGF2 gene were examined in this study. A summary of the results of this thesis shows that a maternal duplication of the region 11p15.5 can be found in approximately 5% of the SRS-patients. This leads to the assumption that imprinted genes of the region 11p15.5 are involved in the aetiology of the syndrome. A substantial involvement of the genes IGF2 and CDKN1C could be ruled out in this study. However, a correlation between known variants of the IGF2 gene and SRS could not be clarified completely, so that further studies on larger collectives of controls and SRS-patients are needed in the future. Furthermore changes in imprinting patterns as well as mutations of other growth-regulating genes in the region 11p15.5 should be analysed.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2006

Author dc:creator

• Obermann, Caitriona

Contributors dc:contributor

• Eggermann, Thomas

• info:eu-repo/classification/ddc/610
• Medizin
• Silver-Russell-Syndrom

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123261%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:61618