Molecular genetics of X-linked cone-rod dystrophy and Åland Island eye disease

Inherited retinal diseases are the most common cause of vision loss among the working population in Western countries. It is estimated that ~1 of the people worldwide suffer from vision loss due to inherited retinal diseases. The severity of these diseases varies from partial vision loss to total blindness, and at the moment no effective cure exists. To date, nearly 200 mapped loci, including 140 cloned genes for inherited retinal diseases have been identified. By a rough estimation 50% of the retinal dystrophy genes still await discovery. In this thesis we aimed to study the genetic background of two inherited retinal diseases, X-linked cone-rod dystrophy and Åland Island eye disease. X-linked cone-rod dystrophy (CORDX) is characterized by progressive loss of visual function in school age or early adulthood. Affected males show reduced visual acuity, photophobia, myopia, color vision defects, central scotomas, and variable changes in fundus. The disease is genetically heterogeneous and two disease loci, CORDX1 and CORDX2, were known prior to the present thesis work. CORDX1, located on Xp21.1-11.4, is caused by mutations in the RPGR gene. CORDX2 is located on Xq27-28 but the causative gene is still unknown. Åland Island eye disease (AIED), originally described in a family living in Åland Islands, is a congenital retinal disease characterized by decreased visual acuity, fundus hypopigmentation, nystagmus, astigmatism, red color vision defect, myopia, and defective night vision. AIED shares similarities with another retinal disease, congenital stationary night blindness (CSNB2). Mutations in the L-type calcium channel α1F-subunit gene, CACNA1F, are known to cause CSNB2, as well as AIED-like disease. The disease locus of the original AIED family maps to the same genetic interval as the CACNA1F gene, but efforts to reveal CACNA1F mutations in patients of the original AIED family have been unsuccessful. The specific aims of this study were to map the disease gene in a large Finnish family with X-linked cone-rod dystrophy and to identify the disease-causing genes in the patients of the Finnish cone-rod dystrophy family and the original AIED family. With the help of linkage and haplotype analyses, we could localize the disease gene of the Finnish cone-rod dystrophy family to the Xp11.4-Xq13.1 region, and thus establish a new genetic X-linked cone-rod dystrophy locus, CORDX3. Mutation analyses of candidate genes revealed three novel CACNA1F gene mutations: IVS28-1 GCGTC>TGG in CORDX3 patients, a 425 bp deletion, comprising exon 30 and flanking intronic regions in AIED patients, and IVS16+2T>C in an additional Finnish patient with a CSNB2-like phenotype. All three novel mutations altered splice sites of the CACNA1F gene, and resulted in defective pre-mRNA splicing suggesting altered or absent channel function as a disease mechanism. The analyses of CACNA1F mRNA also revealed novel alternative wt splice variants, which may enhance channel diversity or regulate the overall expression level of the channel. The results of our studies may be utilized in genetic counseling of the families, and they provide a basis for studies on the pathogenesis of these diseases. In the future, the knowledge of the genetic defects may be used in the identification of specific therapies for the patients.

Helsingin lämpösaareke ajallisena ja paikallisena ilmiönä

The urban heat island phenomenon is the most well-known all-year-round urban climate phenomenon. It occurs in summer during the daytime due to the short-wave radiation from the sun and in wintertime, through anthropogenic heat production. In summertime, the properties of the fabric of city buildings determine how much energy is stored, conducted and transmitted through the material. During night-time, when there is no incoming short-wave radiation, all fabrics of the city release the energy in form of heat back to the urban atmosphere. In wintertime anthropogenic heating of buildings and traffic deliver energy into the urban atmosphere. The initial focus of Helsinki urban heat island was on the description of the intensity of the urban heat island (Fogelberg 1973, Alestalo 1975). In this project our goal was to carry out as many measurements as possible over a large area of Helsinki to give a long term estimate of the Helsinki urban heat island. Helsinki is a city with 550 000 inhabitants and located on the north shore of Finnish Bay of the Baltic Sea. Initially, comparison studies against long-term weather station records showed that our regular, but weekly, sampling of observations adequately describe the Helsinki urban heat island. The project covered an entire seasonal cycle over the 12 months from July 2009 to June 2010. The measurements were conducted using a moving platform following microclimatological traditions. Tuesday was selected as the measuring day because it was the only weekday during the one year time span without any public holidays. Once a week, two set of measurements, in total 104, were conducted in the heterogeneous temperature conditions of Helsinki city centre. In the more homogeneous suburban areas, one set of measurements was taken every second week, to give a total of 52.The first set of measurements took place before noon, and the second 12 hours, just prior to midnight. Helsinki Kaisaniemi weather station was chosen as the reference station. This weather station is located in a large park in the city centre of Helsinki. Along the measurement route, 336 fixed points were established, and the monthly air temperature differences to Kaisaniemi were calculated to produce monthly and annual maps. The monthly air temperature differences were interpolated 21.1 km by 18.1 km horizontal grid with 100 metre resolution residual kriging method. The following independent variables for the kriging interpolation method were used: topographical height, portion of sea area, portion of trees, fraction of built-up and not built-up area, volumes of buildings, and population density. The annual mean air temperature difference gives the best representation of the Helsinki urban heat island effect- Due to natural variability of weather conditions during the measurement campaign care must be taken when interpretation the results for the monthly values. The main results of this urban heat island research project are: a) The city centre of Helsinki is warmer than its surroundings, both on a monthly main basis, and for the annual mean, however, there are only a few grid points, 46 out of 38 191, which display a temperature difference of more than 1K. b) If the monthly spatial variation is air temperature differences is small, then usually the temperature difference between the city and the surroundings is also small. c) Isolated large buildings and suburban centres create their own individual heat island. d) The topographical influence on air temperature can generally be neglected for the monthly mean, but can be strong under certain weather conditions.