Genetics of inherited small vessel diseases – in search of a novel small vessel disease and modifiers of the clinical course of CADASIL

The genetic and environmental risk factors of vascular cognitive impairment are still largely unknown. This thesis aimed to assess the genetic background of two clinically similar familial small vessel diseases (SVD), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) and Swedish hMID (hereditary multi-infarct dementia of Swedish type). In the first study, selected genetic modifiers of CADASIL were studied in a homogenous Finnish CADASIL population of 134 patients, all carrying the p.Arg133Cys mutation in NOTCH3. Apolipoprotein E (APOE) genotypes, angiotensinogen (AGT) p.Met268Thr polymorphism and eight NOTCH3 polymorphisms were studied, but no associations between any particular genetic variant and first-ever stroke or migraine were seen. In the second study, smoking, statin medication and physical activity were suggested to be the most profound environmental differences among the monozygotic twins with CADASIL. Swedish hMID was for long misdiagnosed as CADASIL. In the third study, the CADASIL diagnosis in the Swedish hMID family was ruled out on the basis of genetic, radiological and pathological findings, and Swedish hMID was suggested to represent a novel SVD. In the fourth study, the gene defect of Swedish hMID was then sought using whole exome sequencing paired with a linkage analysis. The strongest candidate for the pathogenic mutation was a 3’UTR variant in the COL4A1 gene, but further studies are needed to confirm its functionality. This study provided new information about the genetic background of two inherited SVDs. Profound knowledge about the pathogenic mutations causing familial SVD is also important for correct diagnosis and treatment options.Perinnöllisten aivojen pienten suonten tautien genetiikkaa – uuden taudin geneettinen tausta ja CADASILIN taudinkuvaa muuntelevat tekijät Verisuoniperäisistä häiriöistä johtuvan kognition heikentymisen syntyyn vaikuttavia geneettisiä ja ympäristötekijöitä tunnetaan toistaiseksi vähän. Tässä työssä tutkittiin kahden kliinisesti samankaltaisen aivojen pienten suonten taudin, CADASILin (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) ja ruotsalaisessa suvussa esiintyvän perinnöllisen multi-infarktidementian (Swedish hMID) genettistä taustaa. Ensimmäisessä osatyössä CADASILin taudinkuvaan vaikuttavia tekijöitä tutkittiin 134:n samaa NOTCH3-geenin mutaatiota (p.Arg133Cys) kantavan suomalaisen potilaan aineistossa. Potilaiden apolipoproteiini E (APOE) -genotyypit, angiotensinogeeniä koodittavan geenin (AGT) p.Met268Thr-polymorfia ja kahdeksan NOTCH3-polymorfiaa tutkittiin, mutta minkään niistä ei voitu osoittaa assosioituvan potilaan ensimmäisen aivoinfarktin tai migreenin kanssa. Toisessa osatyössä tupakointi, statiinilääkitys ja aktiivinen liikunta osoittatutuivat merkittävimmiksi eroiksi elintavoissa taudinkuvaltaan toisistaan poikkeavien CADASILia sairastavien identtisten kaksosten välillä. Kolmannessa osatyössä ruotsalaisen multi-infarktidementiaa sairastavan suvun CADASIL-diagnoosi osoitettiin vääräksi geneettisten, radiologisten ja patologisten tutkimusten perusteella. Neljännessä osatyössä pyrittiin selvittämään tämän taudin taustalla oleva geenivirhe eksomisekvensoinnin ja kytkentäanalyysin avulla. Tutkimusten perusteella lupaavin variantti sijaitsee COL4A1-geenin 3’UTR-alueella. Koska kyseessä on UTR-alueen variantti, lisätutkimukset ovat tarpeen variantin patogeenisyyden osoittamiseksi. Tämä tutkimus valotti kahden perinnöllisen vaskulaarisen taudin geneettistä taustaa. Taudin aiheuttavan geenivirheen ja taudinkuvaa muuntelevien tekijöiden tunteminen helpottaa sairauksien diagnostiikkaa ja uusien hoitomuotojen kehittämistä.Siirretty Doriast

A Novel Loss-of-Function GRN Mutation p.(Tyr229*) : Clinical and Neuropathological Features

Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.Peer reviewe

CADASIL and CARASIL

Peer reviewe

Copy number alterations define outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

Funding Information: NGS library preparation, sequencing and sequence analysis were performed by the Institute for Molecular Medicine Finland (FIMM) Technology Center, University of Helsinki. We thank laboratory technicians Jay Klievink in Hematology Research Unit Helsinki (HRUH) and Minna Suvela in FIMM for technical support with the DNA extractions and laboratory coordinator Minna Tuominen in FIMM for technical support with multiplex ligation-dependent probe amplification. We are grateful to the members of the HRUH for discussions and technical help. We thank research nurses Anne Gesterberg, Jenni Raali and Susanna Helkkula for help with clinical data. We thank Dr Veli Kairisto in Tykslab, Dr Taru Kuittinen in Kuopio University Hospital and clinical laboratory geneticists Anne Juvonen and Tarja Salonen in HUSLAB for help with clinical samples. The samples of this project were provided by Finnish University Hospital clinical laboratories and the Finnish Hematology Registry and Clinical Biobank (FHRB) with appropriate ethics approval (Dnro 202/06.01.00/2013). We thank all the patients for their generous participation. The FHRB Biobank is supported by the Finnish Association of Hematology, the Finnish Red Cross Blood Service, Institute for Molecular Medicine Finland, and the participating hospitals in Finland. This study was supported by the Doctoral Program in Clinical Research at the University of Helsinki and personal grants (to HH) from Emil Aaltonen Foundation, Ida Montin Foundation, Blood Disease Research Foundation, Finnish Hematology Association, Finnish Medical Foundation, Biomedicum Helsinki Foundation, Paulo Foundation, (to SM) Finnish Cancer Organizations, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, and state funding for university-level health research in Finland. The laboratory analytics costs of this study were funded by Incyte. Funding Information: TS (not related to this study) is a member of the advisory board of Celgene and AbbVie; is a member of the advisory board of and received lecture fees from Pfizer and Janssen-Cilag; received lecture fees from Bristol Myers Squibb; received congress fees from and is a member of the advisory board of Novartis; received congress fees from Amgen. MP (not-related to this study) is a member of the advisory board of Pfizer and AbbVie; received lecture and congress fees from Novartis. OB received consultancy fees from Novartis and Sanofi. SM (not related to this study) received research funding from Novartis, BMS, Janpix, and Pfizer. All other authors have no conflicts of interest to disclose. Funding Information: NGS library preparation, sequencing and sequence analysis were performed by the Institute for Molecular Medicine Finland (FIMM) Technology Center, University of Helsinki. We thank laboratory technicians Jay Klievink in Hematology Research Unit Helsinki (HRUH) and Minna Suvela in FIMM for technical support with the DNA extractions and laboratory coordinator Minna Tuominen in FIMM for technical support with multiplex ligation-dependent probe amplification. We are grateful to the members of the HRUH for discussions and technical help. We thank research nurses Anne Gesterberg, Jenni Raali and Susanna Helkkula for help with clinical data. We thank Dr Veli Kairisto in Tykslab, Dr Taru Kuittinen in Kuopio University Hospital and clinical laboratory geneticists Anne Juvonen and Tarja Salonen in HUSLAB for help with clinical samples. The samples of this project were provided by Finnish University Hospital clinical laboratories and the Finnish Hematology Registry and Clinical Biobank (FHRB) with appropriate ethics approval (Dnro 202/06.01.00/2013). We thank all the patients for their generous participation. The FHRB Biobank is supported by the Finnish Association of Hematology, the Finnish Red Cross Blood Service, Institute for Molecular Medicine Finland, and the participating hospitals in Finland.Non peer reviewe

Copy number alterations define outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

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Comparative Typing of Campylobacter jejuni by Heat-Stable Serotyping and PCR-Based Restriction Fragment Length Polymorphism Analysis

Campylobacter jejuni has become the most common bacterial cause of human gastroenteritis worldwide. Rapid, discriminatory typing methods are required to identify potential clusters of infections. The major disadvantage of the well-evaluated and widely used Penner heat-stable serotyping method is the high level of nontypeability. The correlation of the types determined by the Penner heat-stable serotyping method and PCR-based restriction fragment length polymorphism (RFLP) analysis of the lipooligosaccharide (LOS) biosynthesis genes of C. jejuni was studied with 149 C. jejuni strains. Of these strains, 79 were patient strains belonging to 25 Penner serotypes, 60 were nontypeable patient strains, and 10 were reference strains. A 9.6-kb DNA fragment of the LOS gene cluster was amplified and digested with the restriction enzymes HhaI and DdeI. Altogether, 39 different RFLP types (including 30 HhaI profiles and 32 DdeI profiles) were identified. Type Hh1Dd1 was the most common type, with 36% of the strains and strains of 12 serotypes being of this type. A high level of discrimination was obtained, and a correlation between the Penner serotypes and the PCR-RFLP types could be seen. Also, variation in the LOS biosynthesis genes within a single Penner serotype was found. Although the PCR-RFLP method may not be sufficient to compensate for Penner serotyping, it can give valuable information about nontypeable strains and further characterize strains of common serotypes