Application of molecular techniques in population genetic studies of cystic fibrosis in the Netherlands de Vries, Hendrik Gerardus

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1 University of Groningen Application of molecular techniques in population genetic studies of cystic fibrosis in the Netherlands de Vries, Hendrik Gerardus IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1996 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): de Vries, H. G. (1996). Application of molecular techniques in population genetic studies of cystic fibrosis in the Netherlands [S.l.]: [S.n.] Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Application of molecular techniques in population genetic studies of cystic fibrosis in The Netherlands

3 Stichting Drukkerij Regenboog, Groningen This study was supported by a grant from The Netherlands Organization for Scientific Research (NWO). Financial support to publish this thesis was provided by the NWO and by the "Stichting voor erfelijkheidsvoorlichting te Groningen".

4 RIJKSUNIVERSITEIT GRONINGEN Application of molecular techniques in population genetic studies of cystic fibrosis in The Netherlands Proefschrift ter verkrijging van het doctoraat in de Geneeskunde aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus Dr. F. van der Woude in het openbaar te verdedigen op woensdag 31 januari 1996 des namiddags te 2.45 uur precies door Hendrik Gerardus de Vries geboren op 14 april 1965 te Roosendaal

5 Promotores: Prof.dr. L.P. ten Kate Prof.dr. C.H.C.M. Buys Referent: Dr. H. Scheffer

6 Kom verder, zei hij (professor Sickbock) vriendelijk. U treft het. Ik ben net bezig aan een onderzoek van de mutaties in de genen. Van de wat? vroeg heer Ollie, bedremmeld om zich heen kijkend. Laat maar, hernam de professor. Ik heb ontdekt, dat alles wat de natuur ons voorschotelt beuzelachtig is. Er bestaat niets, dat door een scherp geleerde niet kan worden verbeterd. Volgt u me? (Marten Toonder; Een heer moet alles alleen doen; De toornviolen. De Bezige Bij, Amsterdam, 1969)

7 Promotiekommissie: Prof.dr. J.J. Cassiman Prof.dr. A. Hofman Prof.dr. H.S.A. Heymans

8 Contents Outline of this thesis Chapter 1. General introduction 1.1 Delineation of and research into cystic fibrosis The CFTR gene and its mutations Possibilities for genetic modification A. Mouse models 15 B. Somatic gene therapy for cystic fibrosis Cystic fibrosis prevalence at birth What causes the high frequency of cystic fibrosis? Screening for cystic fibrosis carriers Identity By Descent (IBD) analysis 21 References 23 Chapter 2 Validation of determination of F508 mutations of the cystic 33 fibrosis gene in over 11,000 mouthwashes. Chapter 3 Prevalence of F508 cystic fibrosis carriers in The Netherlands: 41 region of residence, age, and number of offspring as explanatory variables.

9 Chapter 4 Relative frequencies of CFTR mutations in The Netherlands: 57 Regional variation is present even in a small country. Chapter 5 Number and sex of offspring of F508 carriers outside cystic 67 fibrosis families Chapter 6 Haplotype identity between individuals who share a CFTR 71 mutation allele Identical By Descent: demonstration of the usefulness of the haplotype sharing concept for gene mapping in real populations Summary 85 Samenvatting 89 Curriculum vitae 94 Dankwoord 95

10 Outline of this thesis Cystic fibrosis (CF) is a common autosomal recessive disease with an estimated birth prevalence of about one in 2500 in Caucasian populations. Since the cloning and characterizing of the CF gene in 1989, numerous reports have been published on the detection of new mutations. Till now more then 500 mutations have been described and this number is still increasing. The most common CF mutation is the F508 mutation with an estimated relative frequency of 70% in Europe. The median life expectancy of CF patients has strongly increased to years. Since 1991 the genetic modification is intensively investigated in mouse-models and in somatic gene therapy studies. The birth prevalences of CF in European populations and populations of European descent elsewhere show a range from 1 in 1700 to 1 in 7700 (excluding Finland where CF is extremely rare). Heterozygote advantage is the most likely explanation for the maintenance of the high CF gene frequency at current levels. The feasibility and appropriateness of offering carrier testing to the general population was and still is the topic for extensive discussions. This resulted in a number of arguments against and in favour of population screening. The American Society of Human Genetics and the National Institutes of Health stated that carrier screening would be desirable only if 90-95% of the mutations can be detected. The distribution of numerous less common CF mutations is limited to certain countries or even population groups within countries. It has been well described that some specific mutations have achieved a high frequency in certain founder populations. An example is the A455E mutation in a French Canadian population. It is very likely that patients with this mutation have a common not to far predecessor. The study of the DNA of patients with this mutation has been used to demonstrate the general feasibility of an Identity By Descent (IBD) approach. The application of molecular techniques strongly enhances the identification of CF patients. Direct mutation detection can also be used for epidemiologic studies and population-based carrier screening. One of the purposes of this study was to analyse the usefulness of a mouthwash procedure for the detection of a large numbers of CF carriers. Chapter 2 describes the determination of the failure rate, specificity and sensitivity of the mouthwash procedure. The samples collected for 9