FINNISH DISEASE HERITAGE

Transcription

1 1 Faculty of Biochemistry and Molecular Medicine: Molecular, cell biological and genetic aspects of diseases FINNISH DISEASE HERITAGE Sanna Karppinen Marjo Kestilä & Minna Männikkö, Heli Ruotsalainen & Sanna Karppinen

2 Content of the lecture: Finnish disease heritage History and origin 3 Identification of genes and 18 examples of diseases From gene to function and 30 pathogenesis Genetic testing 35 Questions 40 2 Aims for this lecture: to learn what is ment by Finnish disease heritage and the characteristics and origin of it to get familiar with some diseases of Finnish disease heritage to understand why it is important to study also rare diseases

3 3 History of the Finnish Disease Heritage

4 What means Finnish disease heritage? includes 36 genetic diseases that are more common in Finland than in elsewhere in the world on the other hand, some common diseases in other parts of the world are rare in Finland FinDis Finnish Disease Database 4 findis.org

5 How the story started? Congenital Nephrotic Syndrome of the Finnish Type 5 large placenta massive proteinuria kidney specific lethal without kidney transplantation

6 6 Possible pathogene? Environment and lifestyle Swamp near the house Tapeworm Bathing habbit (sauna) Illnesses of mother Other diseases Something else?

7 7 CNF thesis study of Reijo Norio : Inherited autosomal recessive 57 families

8 1972 ja 1973 Reijo Norio, Harri Nevanlinna, Jaakko Perheentupa 8 Finnish disease heritage Consist of rare diseases caused by mutation in a single gene. Each disease is more common in Finland than elsewhere in the world.

9 Perheentupa s steps: from 1950 s 9

10 Until now : Salla disease 10 Kuusamo: Schizophrenia Kuusamo-Kainuu-Koilismaa: Northern epilepsy Multiple sclerosis: higher incidence in Southern Ostrobothnia, no own gene found Cohen syndrome Heart arrhythmia causing sudden death Finnish amyloidosis Iltasanomat

11 11 Model of inheritance Monogenic Autosomal recessive: 32 Autosomal dominant: 2 X-chromosomal: 2 Autosomal recessive 25 % of children affected Autosomal dominant 50 % of children affected

12 Clinical features Severe of progressive mental retardation 1/3 12 Lethal during fetal period or in childhood INCL CLN5 AGU SALLA PLO-SL EPMR PEHO IOSCA CHS MEB GRACILE LCCS HYDROLET MKS (CNF) Anemia Autoimmune disease Visual handicap Hearing defects Infertility problem Growth defect Metabolic disturbances Skeletal disturbances Diarrhea

13 Why Finland has its specific pattern of inherited diseases? 13

14 14 Origin of Finnish disease heritage History of Finnish population genetics and inhabitation Founder effect Genetic drift Bottle neck phenomenon Population movement Geographical and cultural/linguistic isolation National isolation due to geopolitical status Regional isolation due to large area, sparse population and terrain Enrichment of disease causing mutations by chance

15 15 Founder effect, genetic drift and bottle neck founder effect means that when a new population originates from few individuals only, this new population gets no more than a small random sample from the genes of the primary populatio The genes of different subpopulations originating from the same primary population thus differ greatly from each other. genetic drift influences the genetic pools of small subpopulations by chance chance has a role in determining whether a given individual survives and reproduces or not gene variants may become common or disappear completely Effect in small populations is high bottleneck phenomenon is a special case of the founder effect and the genetic drift. A large population may diminish into a small fraction due to a war or an epidemic. In the remaining part of the population that has passed through this bottleneck, founder effect and genetic drift may act as in a freshly- formed small subpopulation.

16 16 Origin of Finnish disease heritage Founder effect About years ago a small ground population and its genetic material Inhabitation history of Finland Two bottle necks: 1. Hunters and collectors, about 3000 inhabitants, 4000 years ago started to move and changed the way of living in these areas to agriculture 2. People moved to north and east in 16th century after which the genetic pool of the new population centers was modified by chance Population isolates Some genetic mutations were enriched regionally In 18th century population size was , living in isolated villages, little movement, marriages between relatives In 20th century people moved to cities migration diseases are now found in different parts of Finland (Peltonen L et al., 2000)

17 17 Incidence 1: : / year Regionally different new vs. old mutation a) Congenital chloride diarrhrea : Synnynnäinen kloridiripuli: b) CNF, Suomalaistyyppinen synnynnäinen nefroosi c) Meckel s syndroome d) Finnish variat of infantile ceroid lipisfuscinosis Suomalainen muunnos infantiilista seroidi lipofuskinoosista Hum Genet. 2003;112(5-6):

18 18 Gene identification an international success story of Finnish genetics

19 GRACILE (vastasyntyneen kuolema) LAAHD (sikiöaikainen kuolema) FSH-RO (hormonipuutos) EPMR (etenevä kehitysvammaisuus) PEHO (etenevä kehitysvammaisuus) TMD (lihassairaus) dominantti RAPADILINO (kasvuhäiriö) LCCS (sikiöaikainen kuolema) IOSCA (etenevä kehitysvammaisuus) CHS (etenevä kehitysvammaisuus) CLN5 (etenevä kehitysvammaisuus) HYDROLET (sikiöaikainen kuolema) SALLA (etenevä kehitysvammaisuus) MECKEL (sikiöaikainen kuolema) MEB (vakava kehitysvammaisuus) TCD, CHM (silmäsairaus), X-kromosomaalinen INCL (etenevä kehitysvammaisuus) GA, HOGA (silmäsairaus) MUL (kasvuhäiriö) DTD (kasvuhäiriö) CHH (kasvuhäiriö) FAF (silmä-, hermo- ja ihosairaus) dominantti USH3 (korva- ja silmäsaiarus) AGU (etenevä kehitysvammaisuus) CLD (ripuli) NKH (vakava kehitysvammaisuus) LPI (metabolinen sairaus) CCD (ripuli) PLO-SL (etenevä kehitysvammaisuus) APECED (autoimmuuni polyendokrinopatia) RESCH, RS (silmäsairaus), X-kromosomaalinen EPM1 (neurologinen sairaus) SMB12 (anemia) CNA2 (silmäsairaus) CNF (munuaissairaus) Geeni kloonattu - mutaatio(t) tunnetaan Geenin sijainti tunnetaan ( Geenin sijainti ei tiedossa )

20 20 EXAMPLE OF DISEASES Hum Genet May;112(5-6): Epub 2003 Mar 8. The Finnish Disease Heritage III: the individual diseases. Norio R 1.

21 21 Youngest mutations Appeared years ago, generations ago Enriched in certain geographical regions Genealogy matches with the distribution of mutation The rarest diseases, incidence 1/ / vlincl

22 22 Genealogy (sukututkimus) Genealogy pedigrees based on church registers starting from 1700 century Information about families and their living areas Relationships within a family and living places Relationships to other families with the same disease

23 23 vlincl 13q22, CLN5 Variant form of Late Infantile Neuronal Ceroid Lipofuscinosis vlincl Fin-major 94% 2467delAT Tyr392Stop Accumulation lipofuscin tissues Develoments slows down at the age 4-7 years Progressive Visual problems, convulsions Average lifetime years Only in Finland

24 vlincl 13q22, CLN Lapua Kuortane 24 Kuortane 1682 Kauhava 1638 Kauhajoki Kurikka Kurikka vlincl (variant late infantile ceroid lipofuscinosis) Carrier frequency Southern Ostrobothia 1:44 Oulu region 1:183 Helsinki region 1:1000 T.Varilo T.Varilo

25 25 Middle aged mutations years ago, generations ago Distribution follows the migration from south-east to west and north Incidence 1/ / spread by the migration in the 16th century Late Settlement

26 PLOSL - Hakola disease 19q13.1, DAP12 = TYROPB, required in tyrosine metabolism Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy PLOSL Fin-major 100% in Finland Deletion of 4 exons Begins at middle-age, leads to death in a couple of years Dementia and cyst-like bone changes Same disease is also caused by mutations in TREM2 gene (non-finn patients ) 26

27 27 Oldest mutations Settling into villages years, generations ago Distribution follows the population frequency Most common ones incidence 1: :18 000

28 Infantile neuronal ceroid lipofuscinosis (INCL) 1p32, PPT gene Santavuori-Haltia disease INCL Fin-major 98 % 364A>T Arg122Trp Development normal for the first 8 18 months After 6-18 months start to regress both physically and mentally At months: motor skills and speech are lost blindness (optic atrophy) muscle twitches and seizures (epilepsy) 3-4 year: severe mental and physical retardation 28 The average lifespan is 9 11 years Prevalence in Finland >130 patients, 1:15000

29 INCL PPT1 = palmitoyl protein thioesterase 29 involved in the catabolism of lipid-modified proteins during lysosomal degradation removes thioester-linked fatty acyl groups such as palmitate from cysteine residues Depalmitoylation of palmitoylated proteins Degradation by lysosomal hydrolases Nature Neuroscience Volume: 16: (2013)

30 Why to study? Story of the Congenital Nephrotic Syndrome of the Finnish Type (CNF) Understanding the mechanism of pathogenesis In vitro models Animal models 30 Etiology (specific mutation) vs. pathogenesis (mechanism) gene protein function pathogenesis

31 31 There are million nephrons in a kidney... When glomerulus is affected: Water and metabolic waste are not secreted Kidney dysfunction Plasma proteins leak to urine Severe proteinuria leads to nephrotic syndrome Enduring proteinuria leads to kidney dysfunction

32 32 Proteins of slit diaphragm Blood Filtration Urine H.Jalanko

33 NPHS1 gene, Finnish mutations 33 Fin-major CT deletion, exon 2 reading frame shift Fin-Minor R1109X exon 26 H.Jalanko

34 CNF studies: AFP vs DNA From possibly wrong diagnosis to right one 34 Conclusions: alphafetoprotein Identification of nephrin started a podocentric era in kidney research Podocytes have a strict quality control Knowledge about the normal function of kidney filtration unit and pathogenesis of renal diseases has significantly increased Patrakka et al. 2002

35 35 Carrier analysis Who When Why? Everybody carries mutations Enriched in certain area Analysis before pregnancy In recessive disease risk 25% per pregnancy > tests yearly DNA Fetal diagnostics from placenta or amniotic fluid sample, pre-implantation samples (risk families) Carrier diagnostics for relatives: siblings of the patient, cousins and their spouses Most of the diseases cause severe handicap and a heavy burden to the patient and the family Norio 2003

36 Genetic testing- general considerations The result of mutation testing is certain, final and irreversible! To consider: Do you want to know about your potential risk to have a certain disease? Will testing reveal something that you wouldn t want to know? With whom you will share the information? Do you have to consider the opinion of some other people before testing? What and how much genetic analysis can tell about you? What is the influence of environment and lifestyle on the risk to get ill? Can the results of gene testing be used against you (employer, insurance company)? 36

37 Why to study diseases/genes of Finnish disease heritage? 37 Better diagnostics approaches available (DNA based) Embryo diagnostics also possible Carrier diagnostics New genes and proteins have been found When the consequence of defective gene/protein is known, new informations about the relevance of the gene/protein is also obtained under normal conditions Based on the pedigree, the risk of the relatives as being carriers of the disease gene can be evaluated More knowledge about molecular mechanisms better treatments in the future?

38 38 More information

39 39 Finnish disease heritage AGU eli aspartyyliglukosaminuria APECED eli autoimmuunipolyendokrinopatiakandidiaasiekto dermidystrofia B12-vitamin selective malabsorption (Imerslund-Gräsbeck s disease) Cohen s syndrome Cornea plana congenita Diastrophic dysplasia FSH-RO (follikkelia stimuloivalle hormonille reagoimattomat ovaariot) GRACILE-syndrome HOGA eli hyperornitinemia Herva s disease Hydroletalus syndrome INCL eli infantile neuronal seroidi-lipofuskinose IOSCA-syndrome Jansky-Bielschowsky, Finnish form Korioideremia LPI (lysinuurinen proteiini-intoleranssi) MEB (lihas-silmä-aivo-oireyhtymä) Meckel s syndrome Meretoja disease Mulibrey-nanism NKH (nonketoottinen hyperglysinemia) PEHO syndrome PLO-SL (polykystinen lipomembranoottinen osteodysplasia sklerosoiva leukoenkefalopatia) PME (progressiivinen myoklonusepilepsia) Nordic epilepsy Rapadilino syndrome Retinoskisis Cartilage-hair hypoplasia (Rusto-hiushypoplasia) Salla disease Spielmeyer-Vogt disease (juveniili neuronaalinen lipofuskinoosi) Congenital chloride diarrhea (Synnynnäinen kloridiripuli) Congenital lack of lactase (Synnynnäinen laktaasinpuutos) CNF (synnynnäinen nefroosi) Tibial muscle dystrophy (Tibiaalinen lihasdystrofia) Usher s syndrome Vuopala disease

40 40 Questions What does mean Finnish disease heritage? Which factors affected the enrichment of certain diseases in Finland? How they did that? Why is it useful to study rare diseases?