👤 L Peltonen

The article contains raw and analyzed data related to the research article "Neuronal ceroid lipofuscinosis genes, CLN2, CLN3, CLN5 are spatially and temporally co-expressed in a developing mouse brain" (Fabritius et al., 2014) [1]. The processed data gives an understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN1, CLN2, CLN3 and CLN5 genes in a murine model. The data shows relationship between the expression pattern of these genes during neural development. Immunohistochemistry was used to identify known interneuronal markers for neurotransmission and cell proliferation: parvalbumin, somatostatin subpopulations of interneurons. Non-radioactive in-situ hybridization detected CLN5 mRNA in the hippocampus. Throughout the development strong expression of CLN genes were identified in the germinal epithelium and in ventricle regions, cortex, hippocampus, and cerebellum. This provides supportive evidence that CLN1, CLN2, CLN3 and CLN5 genes may be involved in synaptic pruning. Show less

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Long noncoding RNAs (lncRNA) are involved in various biological processes, and their role in cancer progression is emerging. Whole transcriptome analysis of cSCC cells (n = 8) and normal human epidermal keratinocytes (n = 4) revealed overexpression of long intergenic ncRNA (LINC00162) in cSCC cells. The expression of LINC00162 in cSCC cells was upregulated by inhibition of the p38α and p38δ mitogen-activated protein kinases. Analysis of tissue sections by RNA in situ hybridization showed that LINC00162 is specifically expressed by tumor cells in cSCCs but not by keratinocytes in normal skin in vivo. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells, and suppressed the growth of human cSCC xenografts in vivo. Furthermore, knockdown of LINC00162 inhibited extracellular signal-regulated kinase 1/2 activity and upregulated expression of dual specificity phosphatase 6 (DUSP6) in cSCC cells. Based on these observations, LINC00162 was named p38 inhibited cutaneous squamous cell carcinoma associated lincRNA (PICSAR). Our results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of extracellular signal-regulated kinase 1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a biomarker and putative therapeutic target in cSCC. Show less

Neuronal ceroid lipofuscinosis (NCL) diseases consist of a group of genetically inherited neurodegenerative disorders that share common symptoms such as seizures, psychomotor retardation, blindness, and premature death. Although gene defects behind the NCL diseases are well characterized, very little is known how these defects affect normal development of the brain and cause the pathology of the disease. To obtain understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN2, CLN3 and CLN5 genes was investigated in developing mouse brain. The relationship between the expression pattern and the developmental stage of the brain showed that these genes are co-expressed spatially and temporally during brain development. Throughout the development strong expression of the three mRNAs was detected in germinal epithelium and in ventricle regions, hippocampus and cerebellum, all representing regions that are known to be associated with the formation of new neurons. More specifically, RT-PCR studies on developing mouse cortices revealed that the CLN genes were temporally co-expressed in the neural progenitor cells together with known stem cell markers. This suggested that CLN2, CLN3 and CLN5 genes may play an important role in early embryonal neurogenesis. Show less

Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes. Show less

C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. Show less

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. Show less

Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk. Show less

USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined. We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta (P=0.0028), with TGs in dyslipidemic coronary artery disease subjects (P=0.03), and with high-density lipoprotein cholesterol (P=0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated. Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects. Show less

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. Show less

A possible role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility has been suggested. We tested association of sixteen 19q13 markers with MS in 459 families. Nominally significant associations were tested in an independent set of 323 families as well as in the pooled set of 782 families. We were not able to confirm previously suggested associations with APOE, GIPR, ZNF45, ILT6 and D19S585. In the screening dataset nominally significant associations were found with D19S867 and with APOE haplotype (p=0.007 in both), but these were not replicated in the independent dataset nor in the pooled analysis of 757 families. Thus, we were not able to detect any statistically significant allelic associations. Re-sequencing based approaches may be required for elucidating the role chromosome 19q13 with MS. Show less

Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene-environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci. Show less

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia. Show less

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors. Show less

Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q. Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms. We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p = 1.26 x 10(-5), odds ratio (OR) = 1.47, rs3923809 in BTBD9, p = 4.11 x 10(-5), OR = 1.58 and rs6494696 in MAP2K5/LBXCOR1, p = 0.04764, OR = 1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9. Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering. Show less

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia. Show less

Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 x 10(-8) for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care. Show less

To provide an overview of recent advances that have defined the first putative genes behind familial combined hyperlipidemia, the most common genetic dyslipidemia and a major risk factor for early coronary heart disease. The first locus for familial combined hyperlipidemia on 1q21-23 revealed a gene encoding a transcription factor critical in lipid and glucose metabolism, USF1. All the associated variants represent noncoding single nucleotide polymorphisms, one of which affects the binding site of nuclear proteins with a putative effect on transcript levels of USF1. Transcript analyses of fat biopsies have exposed risk-allele related changes in the downstream genes. Another recent clue to the molecular pathogenesis of familial combined hyperlipidemia is the association of the high triglyceride trait with the APOA5 gene, located on 11q. More familial combined hyperlipidemia genes are expected to be found, since linkage evidence exists for additional loci on 16q24 and 20q12-q13.1. Genetic research of familial combined hyperlipidemia families has revealed several linked loci guiding to susceptibility genes. The USF1 transcription factor is the major gene underlying the 1q21-23 linkage. Modifying genes, especially influencing the high triglyceride trait, include APOC3 and APOA5, the latter representing a downstream target of USF1 and implying a USF1-dependent pathway in the molecular pathogenesis of dyslipidemias. Show less

Neuronal ceroid lipofuscinoses (NCL) are rare neurological disorders with a uniform phenotype, caused by mutations in seven known genes. NCL provide a unique model to characterize molecular pathways critical for normal neuronal development and pathological neuronal degeneration. Systems biology based approach utilizes the rapidly developing tools of genomics, proteomics, lipidomics and metabolomics and aims at thorough understanding of the functions of cells, tissues and whole organisms by molecular analysis and biocomputing-assisted modeling. The systems level understanding of NCL is now possible by utilizing different model organisms. Initial work has revealed disturbed metabolic pathways in several NCL disorders and most analyses have utilized the infantile (INCL/CLN1) and juvenile (JNCL/CLN3) disease modeling and utilized mainly human and mouse samples. To date, the data obtained from transcript and lipidomic profiling has pinpointed the role of lipid metabolism and synaptic function in the infantile NCL. Changes in glutamate utilization and amino acid metabolism have been a common theme emerging from the transcript and metabolite profiling of the juvenile NCL. Further experimental models are being developed and systematic sample collection as well as data integration projects are needed. The combined analyses of the global information should provide means to expose all the NCL-associated molecular pathways. Show less

Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative storage diseases characterized by mental retardation, visual failure, and brain atrophy as well as accumulation of storage material in multiple cell types. The diseases are caused by mutations in the ubiquitously expressed genes, of which six are known. Herein, we report that three NCL disease forms with similar tissue pathology are connected at the molecular level: CLN5 polypeptides directly interact with the CLN2 and CLN3 proteins based on coimmunoprecipitation and in vitro binding assays. Furthermore, disease mutations in CLN5 abolished interaction with CLN2, while not affecting association with CLN3. The molecular characterization of CLN5 revealed that it was synthesized as four precursor forms, due to usage of alternative initiator methionines in translation. All forms were targeted to lysosomes and the longest form, translated from the first potential methionine, was associated with membranes. Interactions between CLN polypeptides were shown to occur with this longest, membrane-bound form of CLN5. Both intracellular targeting and posttranslational glycosylation of the polypeptides carrying human disease mutations were similar to wild-type CLN5. Show less

Positional cloning efforts of genes mutated in Batten disease and in the Finnish type of variant late infantile neuronal ceroid lipofuscinosis resulted in the identification of two novel genes, CLN3 and CLN5, and corresponding gene products that proved to be residents of lysosomes. Although the clinical phenotype of these NCL subtypes differs in the age of onset, average life span and EEG findings, the major component of material accumulating in patients' lysosomes is subunit c of mitochondrial ATPase in both these diseases. The CLN3 and CLN5 genes show ubiquitous expression patterns and are targeted to lysosomes in vitro, but the observed synaptosomal localization of the CLN3 protein in neurons would suggest some cell specificity in targeting and function of these proteins. So far, 31 different mutations of the CLN3 gene have been described in Batten patients, with one deletion of 1.02 kb accounting for 75% of disease alleles worldwide. Four CLN5 mutations are known, with one premature stop representing the major founder mutation in the isolated Finnish population. Functional studies of the yeast homolog of CLN3 and increased pH in patients' lysosomes would suggest an involvement of this protein in lysosomal pH homeostasis. Knock-out mouse models for CLN3 have been produced and the histopathology bears a close resemblance to human counterparts with characteristic lysosomal accumulations. Both CLN3 and CLN5 mouse models will provide experimental tools to resolve the pathological cascade in these neurodegenerative diseases. Show less

Familial combined hyperlipidemia (FCHL) is the most frequent familial lipoprotein disorder associated with premature coronary heart disease. However, no genetic defect(s) underlying FCHL has been identified. A linkage between FCHL and the apoA-I/C-III/A-IV gene cluster has been reported but not verified in other populations. A recent study identified FCHL susceptibility haplotypes at this gene cluster. To study whether such haplotypes are also associated with FCHL susceptibility in Finns, we studied 600 well-defined Finnish FCHL patients and their relatives belonging to 28 extended FCHL families by using haplotype, linkage, sib-pair, and linkage disequilibrium analyses. The genotypes of the MspI polymorphisms were associated with total serum cholesterol (P<0.01) and apoB (P<0.05) levels in spouses, which represent the general Finnish population. However, no evidence of direct involvement of any of these loci or their specific haplotypes in the expression of FCHL in the Finnish FCHL families was found. Show less

Apolipoprotein A-IV (apoA-IV) is a glycoprotein constituent of triglyceride-rich and high-density lipoproteins (HDL) and may thus play an important role in lipid metabolism. In Finland two common isoforms (A-IV-1 and A-IV-2) of apoA-IV have been found. The isoforms are the result of the G to T substitution in the third base of the codon 360 in the apoA-IV-2 allele of the apoA-IV gene. The purpose of the study was to determine the apoA-IV allele frequencies in the Saami and the Finns, and to relate the apoA-IV phenotypes to serum lipids. The sample was drawn in connection with a Reindeer Herders' Health Survey performed in northern Finland in 1989. The study group included 248 men with known ethnic origin, Saami and Finns, who lived in the area of the nine northernmost municipalities of Finland. ApoA-IV phenotypes from 71 Saami (both parents Saami) and 177 Finns (both parents Finns) were determined by isoelectric focusing and Western blotting. Serum lipids were determined enzymatically. ApoA-IV allele frequencies in the Saami and the Finns were for A-IV-1 0.894 vs 0.944 and for A-IV-2 0.106 vs 0.056, respectively (chi2-test, P < 0.05). The effect of the apoA-IV phenotype on serum HDL-cholesterol levels differed significantly between the Saami and the Finns (two-way ANCOVA, interaction between ethnicity and apoA-IV phenotype, P < 0.02). In the Saami, HDL-cholesterol levels were significantly higher in the apoA-IV-2/1 than in the apoA-IV-1/1 phenotypes (ANCOVA, P < 0.05). Mean total cholesterol, low-density lipoprotein (LDL)-cholesterol, apolipoprotein B, HDL-cholesterol and triglyceride levels did not differ statistically significantly between the Saami and the Finns. Yet, there was a trend in the Saami of having higher mean total cholesterol, LDL-cholesterol and apolipoprotein B levels than the Finns among the apoA-IV-2/1 phenotypes, while there was only a small difference in these parameters between the Saami and the Finns among the apoA-IV-1/1 phenotypes. In conclusion, the Saami have a higher frequency of the apoA-IV-2 allele than the Finns and most of the other studied populations. Show less

Batten disease (juvenile-onset neuronal ceroid lipofuscinosis, JNCL), the most common neurodegenerative disorder of childhood, is caused by mutations in a recently identified gene ( CLN3 ) localized to chromosome 16p11.2-12.1. To elucidate the biosynthesis and localization of the CLN3 protein, we expressed CLN3 cDNA in COS-1 and HeLa cell lines. In vitro translation, immunoprecipitation and Western blotting analyses detected an approximately 43 kDa polypeptide. Pulse-chase experiments indicated that the CLN3 protein is synthesized as an N -glycosylated single-chain polypeptide, which was not detected in growth medium. Confocal immunofluorescence microscopy revealed that the CLN3 protein is localized to the lysosomal compartment. These results provide evidence that Batten disease can be classified as a member of lysosomal diseases. Show less

The childhood neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative disorders characterised by progressive visual failure, neurodegeneration, epilepsy and the accumulation of an autofluorescent lipopigment in neurones and other cells. Three main subtypes have been identified according to age of onset, clinical features and ultrastructural morphology. These are infantile NCL (INCL; CLN1), classical late infantile NCL (LINCL; CLN2) and juvenile NCL (JNCL; CLN3). Several atypical forms of late infantile NCL (LINCL) have also been described including a Finnish variant LINCL (CLN5). The CLN2 gene has been excluded from the CLN1, CLN3 and CLN5 loci. A genome search was initiated using a homozygosity mapping strategy in five classical LINCL and two variant LINCL consanguineous families. A common region of homozygosity was identified on chromosome 11p15 in two of the classical families. Analysis of a further 33 classical LINCL families supported linkage in this region (Zmax = 3.07 at theta = 0.06 at D11S1338). A common region of homozygosity was also observed on chromosome 15q21-23 in the two variant LINCL families. Extension of the analysis to include a further seven families of identical ultrastructural phenotype established linkage to this region (Zmax = 6.00 at theta = 0.00 at D15S1020). Show less

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. The biochemical basis of these diseases is unknown. Three main childhood forms are recognized: infantile (Santavuori-Haltia disease, CLN1), late infantile (Jansky-Bielschowsky disease, CLN2), and juvenile (Spielmeyer-Vogt-Sjögren, Batten disease, CLN3). The CLN1 gene has been mapped to chromosome 1p and CLN3 to chromosome 16p by linkage analysis (1, 2). The gene locus causing the classical late infantile form (CLN2) has not yet been mapped but has been excluded from both CLN1 and CLN3 loci (8). About 10% of NCL cases have atypical clinical features with most of these resembling the late infantile form. Show less

Infantile neuronal ceroid-lipofuscinosis (CLN1) is the form of neuronal ceroid-lipofuscinoses (NCL) with the earliest onset of symptoms. The locus of the most common form of these disorders, juvenile NCL (CLN3), has been mapped to chromosome 16. We report here linkage data of the same region in Finnish CLN1 families. Our results indicate that CLN1 is not allelic with CLN3 but represents a different locus, which is not located within about 70 cM in chromosome 16. Show less

The ceroid-lipofuscinoses are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. The underlying biochemical defect is unknown. Batten disease (Spielmeyer-Vogt disease, juvenile onset neuronal ceroid-lipofuscinosis) displays autosomal recessive inheritance. Genetic linkage studies were undertaken to determine the chromosomal location of the Batten disease mutation (CLN3). Following identification of linkage to the haptoglobin locus, linkage analysis has been carried out in 42 families by using DNA markers for loci on the long arm of human chromosome 16. The maximal lod score between Batten disease and the locus D16S148 calculated for combined sexes is 6.05 at a recombination fraction theta = 0.00. Multilocus analysis using five loci indicated the most likely order to be HP-D16S151-D16S150-CLN3-D16S148-D16S147. The maximal location score for CLN3 was 48 (equivalent to a lod score of 10.4) in that interval within this fixed marker map. Show less