5 upcoming PhD theses - summaries

The Dept. of Genetics will see 5 PhD students graduate in November and December 2011. Below are the general summaries. More detailed summaries (in several languages) will soon be available on the University’s website http://dissertations.ub.rug.nl/faculties/medicine/2011/

 

Jorieke van Kammen-Bergman: CHARGE syndrome:molecular diagnosis, clinical aspects and its overlap with Kallmann syndrome

2 November 2011, 16.15h

Summary (separate pdf file [PDF], summaries in both Dutch and English), see also http://irs.ub.rug.nl/ppn/33801425X

 

Gerben Duns: Genetics of clear cell renal cell carcinoma: new tumor suppressor genes and aberrant chromatin regulation

7 December 2011, 14.30h

Summary

Clear cell renal cell carcinoma (ccRCC) is genomically characterized by the frequent loss of the short arm of chromosome 3 (3p), suggesting the presence of tumor suppressor genes (TSGs) in this genomic region. This thesis presents the search for these TSGs.

Using a method called GINI, we identified inactivating mutations in histone methyltransferase gene SETD2, located at 3p21, in several ccRCC samples. SETD2 trimethylates histone 3 at position K36, a modification which has been suggested to be involved in alternative splicing. SETD2 knockdown in renal cells indeed resulted in an apparent change in alternative splicing for a set of genes, several of which are interesting with respect to tumorigenic development.

Targeted exome sequencing of ten primary ccRCC tumors revealed inactivating mutations in the known ccRCC tumor suppressor gene VHL, but also in PBRM1, and BAP1 in six, seven, and one of these tumors, respectively. PBRM1 and BAP1 are both located at 3p21 and code for the chromatin targeting subunit of the SWI/SNF chromatin-remodeling complex and an enzyme involved in histone deubiquitination, respectively. Sequencing of PBRM1 in ccRCC-derived cell lines confirmed its frequent inactivation in ccRCC, suggesting that this is a major TSG for ccRCC.

Thus, 3p harbors several genes that do contribute to ccRCC development. Several of these genes encode proteins that modify histone tails or remodel chromatin, suggesting that aberrant chromatin regulation is a core driver event in the development of ccRCC.

  

Jihane Romanos: Genetics of celiac disease and its diagnostic value

12 December 2011 at 14.30h

Summary

Celiac disease (CD) is a common chronic disorder of the small intestine, resulting from aberrant cellular responses to gluten peptides. Because the disease has highly variable and sometimes vague symptoms, it often remains undiagnosed. CD is a multifactorial disorder with the major genetic risk factor being HLA-DQ2/DQ8 molecules. The aim of this thesis was to discuss the identification and replication of genetic risk variants for CD and to develop a risk model that can improve diagnosis.

Chapter 1 introduces CD, its pathogenesis and its genetic background. Chapter 2 validates a novel HLA-tagSNP approach for high-throughput genotyping in three European populations. Chapter 3 replicates the first genome-wide association findings in an Italian population and shows that CD risk loci are differently associated in different populations. Since CD is a major socio-economic burden on several levels, improved diagnosis and early prevention is sorely needed. Chapter 4 shows how genetic risk profiling could be used as a diagnostic or screening tool for CD. Chapter 5 describes this risk profile based on HLA and 10 non-HLA risk alleles. In chapter 6, we improve and validate this model using 26 and 57 variants and replicate the results in two other types of cohorts. Both studies showed that adding non-HLA risk alleles improves identification of high-risk individuals. In chapter 7, we discuss who can benefit from this genetic profiling and how to improve the accuracy of the risk prediction.

Finally, my thesis shows that risk profiling for CD may well have a clinical application for reliably identifying individuals at high risk for CD.

 

Gosia Trynka: Unlocking the genetics of coeliac disease

14 December 2011, 12.45h

Summary

Coeliac disease is the most common food intolerance disorder, affecting some 1% of Western populations. In genetically susceptible individuals, the presence of gluten peptides, which are abundant in dietary products such as bread and pasta, triggers an immune response that leads to inflammation and damage of the small intestine. The major genetic risk factor is HLA (human leukocyte antigen). Until 2007 only 8 other, non-HLA loci were reported to be associated with coeliac disease. The aim of my research work was to identify more regions conferring genetic susceptibility to the disease.

After a preface and outline of the thesis in Chapter 1, Chapter 2 describes an association study of two loci harbouring genes involved in NF- k B signalling. In Chapter 3, I describe the genetic factors shared bytwo autoimmune diseases, coeliac disease and rheumatoid arthritis. Chapter 4 outlines a large genome-wide association study of multiple European cohorts, which identified 13 additional risk loci. In Chapter 5, I review the genetic progress made in coeliac disease and its shared background with other immune-related diseases. Chapter 6 describes how sequencing-based, dense genotyping allowed fine-mapping of coeliac disease risk regions and identified 13 more regions conferring risk for the disease. In Chapter 7, I describe replicating coeliac loci in a Northern Indian population and how the use of ethnically distinct populations can aid in fine-mapping the causal variants.

My work has brought to a total of 40 the risk loci currently associated with coeliac disease, which cumulatively explain 53% of the disease heritability. This research has improved our understanding of the disease biology and pointed to many immune pathways that are altered in coeliac disease patients.

 

Yunia Sribudiani: Genetic dissection and functional studies in Hirschsprung disease

21 December 2011, 14.30h

Summary

Hirschsprung disease (HSCR) is a congenital neurological condition of the colon. Patients with HSCR have severe and sometimes even life-threatening constipation. This is due to a lack of ganglia that regulate the normal peristaltic movement of the colon. HSCR is considered to be a genetic disorder and 12 genes have now been identified. However, mutations in these genes explain only some of the HSCR patients. My research focused on a better understanding of the nervous system of the colon (the enteric nervous system or ENS) and on finding and characterizing mutations and genes that contribute to disease development.

To gain a better insight into the normal development of the ENS, I isolated progenitor cells of the ENS from embryonic mouse guts and analyzed the expression profiles of these cells. I compared these with the expression profile of the entire gut. This resulted in a list of genes that are essential for ENS development and that are perfect candidate genes for HSCR. I also looked for genes in regions previously identified as containing an HSCR gene. This resulted in one new HSCR gene, which proved to be associated specifically in the Chinese patient population. Finally, I characterized the function of a previously identified common mutation that is present in ~70% of HSCR patients.

My work has yielded new insights into ENS development and the disease process. Moreover, it has provided clues on how a common HSCR mutation contributes to disease development and I have identified numerous candidate genes for HSCR.