Huden är en motståndskraftig vävnad som skyddar kroppen mot fysiska ska-dor och vattenförlust. Cellerna i huden är specialinriktade mot att bygga upp fetter och proteiner som i hudens yttersta del bildar ett skyddande lager. Det är fortfarande till stora delar okänt vilka signaler i cellerna som styr denna bildning och vilka faktorer som behövs för tillverkning och nedbrytning av de nödvändiga byggstenarna.
För att få en ökad förståelse av hudens fysiologi kan man studera de gener som är muterade i ärftliga hudsjukdomar och kartlägga effekterna av muta-tionerna. I det här avhandlingsarbetet har två ovanliga hudsjukdomar stude-rats. Den första sjukdomen, iktyos, kännetecknas av ökad fjällning av huden samt rodnad hud. Den ökade fjällningen tros bero på att huden försöker kompensera en brist i barriären som skyddar mot vattenförlust genom att öka produktionen av celler. Den andra sjukdomen, kallad KLICK, uppvisar ock-så fjällning, men även hudförtjockningar i ett karaktäristiskt mönster. I det här projektet användes en genetisk metod som baseras på att jämföra varia-tioner i arvsmassan mellan flera patienter för att hitta den gen som är mute-rad i respektive sjukdom. I arbetet runt sjukdomen iktyos identifiemute-rades hos patienterna mutationer i Iktyin-genen, i vilken man tidigare hittat mutationer i iktyospatienter. Det som är nytt i den här studien är att mutationer i Iktyin kunde kopplas till specifika förändringar i hudens struktur, vilka identifiera-des med elektronmikroskopi. Vidare framkom det att uttrycket av iktyin-genen ökar när hudens celler mognar, vilket tyder på att Iktyin har en viktig funktion för bildningen av hudens yttersta lager. Analys av huden med elek-tronmikroskopi visade att proteinet som iktyin-genen kodar för befinner sig vid keratinfilament i cellerna och vid molekyler i cellmembranet som fäster mot närliggande celler och alltså utövar sin funktion därifrån. Iktyinets roll i huden är okänd, men dessa fynd ger ytterligare ledtrådar till dess funktion.
I den andra sjukdomen, KLICK, hittades hos patienterna en mutation i närheten av POMP-genen. POMP är nödvändigt för att cellens sopstation, proteasomen, ska kunna bildas i alla kroppen celler. Analyserna i det här arbetet visar att mutationen leder till att POMP-genen översätts till ett delvis förändrat mRNA. mRNA är den molekyl som sedan översätts till det funk-tionella proteinet, men i det här fallet tyder resultaten på att mängden protein
från POMP-mRNA minskar i mogna hudceller. Detta leder i sin tur till att inte tillräckligt med proteasomer kan tillverkas, vilket gör att proteiner inte bryts ner som de ska i huden. Det här tros störa cellernas utmognad, bland annat genom att molekyler som inte har brutits ner korrekt ansamlas och stör cellens funktioner.
Dessa studier har identifierat genetiska förändringar kopplade till två ärft-liga hudsjukdomar, samt även bidragit till ökad förståelse av hudens fysiolo-gi. Att hitta de specifika avvikelserna i sjukdomar är viktigt för att kunna utveckla diagnostik och behandling av patienter. Resultaten från de här stu-dierna kan användas för att arbeta vidare mot detta mål.
Acknowledgements
This work was carried out at the Department of Immunology, Genetics and Pathology at Uppsala University. I wish to express my gratitude to everyone who has contributed to the work leading to this thesis. In particular, I would like to acknowledge:
The patients and their families for their participation in these studies, along with our collaborators throughout Europe that have contributed in various ways.
Niklas Dahl, my supervisor, for introducing me to genetics and basic re-search. Thank you for your solid confidence in me and my ideas (including wild plans about going abroad) and for your ever-lasting optimism about new results and prospects.
Anders Vahlquist, my co-supervisor, for a good collaboration and for bring-ing clinical input to this work. I truly appreciate our discussions to which you have always brought encouragement and enthusiasm.
Present and former members of the Dahl group: Lena, Ed, Maria T, Malin, Larry, Miriam, Jitendra, Anne-Sophie, Hanna, Joakim, Jens, Maria S, Alire-za, Chikari, Jimmy, Doroteya and all the other great students that have come and gone over the years. Thank you all for your generosity, for your support in situations when weeks (months?) of work go down the drain and, most of all, for all the great fun!
Medhi, Ola, Madhu, Maja, Sara and Marie-Louise of the Wadelius and the Bondeson/Annerén groups. I have enjoyed our scientific discussions as well as our relaxed chats over “Friday fikas”.
All other Rudbeckian friends!
Inger Pihl-Lundin, Hans Törmä and Hao Li at the Dep. of Medical Sciences, for contributing with substantial work and discussions to the studies leading to this thesis. I have really enjoyed working with you and I deeply appreciate our collaboration.
Brian Ellis for linguistic help and, above all, for long and lasting friendship.
My old buddies from Umeå and my friends from Medical School for uncon-ditional support in the ups and downs of life.
Åke, Solbritt and Matilda for life-long encouragement and inspiration. Jo-han, Karin, Ulf, Sofia and Ebba for enthusiasm and interest in the seemingly incomprehensible work that I have carried out during the past years.
Oskar, for end-less support, patience and encouragement. You have dried my tears in times of despair, calmed my temper in times of frustration and laughed with me in times of success; you are unreplaceable .
This work was supported by the Swedish Research Council, T. and R.
Söderberg’s fund, E. Welander foundation, Astra Zeneca, Network for Ich-thyoses and Related Keratinisation Disorders (German Ministry of Educa-tion and Research), Science for Life Laboratory, Uppsala University and Uppsala University Hospital.
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