Targeted search for genetic causes of the Prader Willi like phenotype
1 March 2018
Promotiezaal (UAntwerp, Campus Drie Eiken, Building Q) - Universiteitsplein 1 - 2610 Wilrijk (Antwerpen) (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
Wim Van Hul
PhD defence Ellen Geets - Department of Biomedical Sciences
Defined as abnormal or excessive fat accumulation due to an imbalance between energy intake and expenditure, obesity has become a chronic disorder reaching epidemic proportions. In 1973, Coleman and Hummel demonstrated for the first time that genetic factors are involved in the disease. Later on, twin and adoption studies confirmed this and estimated the heritability of obesity at 40 – 70%. However, as obesity is extremely heterogeneous only 2.7% of this heritability could be explained to date.
Over the years, various forms of obesity have been reported including monogenic, complex and syndromic obesity. The Prader Willi syndrome (PWS), caused by a paternal defect in the imprinted region 15q11.2 – q13, is with its prevalence of 1 in 10,000 – 30,000 individuals the most common form of syndromic obesity. Once the clinical diagnosis of PWS cannot be confirmed molecularly, patients are classified as Prader Willi like (PWL). In literature, the PWL phenotype has mostly been associated with deletions on chromosome 6q. By investigating the genetic architecture in this specific study population more in detail, we ultimately want to contribute to the unravelment of the genetic background of obesity.
In the first part we wanted to elucidate the role of SIM1 and MRAP2 in the pathogenesis of PWL and the obesity phenotype seen in these patients by performing copy number variation and mutation analysis of both genes. We did confirm the results of previous studies that SIM1 and MRAP2 could play a role in the PWL phenotype albeit, in our case, in a limited number of patients. In the second and third part the role of MCHR2, OXT and OXTR was examined. Unfortunately, we did not identify any gene-harboring deletions or variants and subsequently suggested that these genes are not major contributors to human obesity nor the PWL phenotype. In the last part, we screened POU3F2 in a cohort of PWL patients and obese children and adolescents which resulted in the identification of three interesting variants. Unfortunately, preliminary results of functional experiments do not gave a clear indication whether the mutations have an effect on the leptin-melanocortin signaling pathway so further functional research is still needed.
In conclusion, we can state that we identified possible disease causing mutations and one new interesting gene, POU3F2, in the pathogenesis of PWL and the obesity phenotype. These results can help in the unravelment of the underlying mechanisms of energy metabolism and ultimately into accurate therapeutic treatment.