Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. ...Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the
Parkin gene, and recently a second gene,
PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by ⩾25 cM, from the more centromeric
PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus,
PARK7, involved in autosomal recessive, early-onset parkinsonism.
Because several macular dystrophies are caused by mutations in the peripherin/RDS gene, we examined autosomal dominant and sporadic cases of central areolar choroidal dystrophy for mutations in the ...peripherin/RDS gene.
DNA sequence analysis of the peripherin/RDS gene was performed in four sporadic cases and in ten affected and nine unaffected individuals from seven families with autosomal dominant central areolar choroidal dystrophy.
An Arg-142-Trp mutation in the peripherin/RDS gene was found in ten affected family members in seven families. Among these, a 69-year-old man with the Arg-142-Trp mutation, who was unaffected six years before blood sample analysis, showed a parafoveal area of chorioretinal atrophy. The 65-year-old sister of this family had the Arg-142-Trp mutation with no macular abnormalities, but she might still develop central areolar choroidal dystrophy at an older age. No mutation was found in the four sporadic cases.
Autosomal dominant central areolar choroidal dystrophy, studied in seven families, is caused by an Arg-142-Trp mutation in the peripherin/RDS gene.
Evidence is accumulating that low levels of IGF-I play a role in the pathogenesis of type 2 diabetes and cardiovascular diseases. We examined the role of a genetic polymorphism in the promoter region ...of the IGF-I gene in relation to circulating IGF-I levels and growth measured as body height, and we studied the relationship of this polymorphism with type 2 diabetes and myocardial infarction. The relation between the IGF-I polymorphism and body height was assessed in a population-based sample of 900 subjects from the Rotterdam Study. Within each genotype stratum, 50 subjects were randomly selected for a study of the relation of this polymorphism with serum IGF-I levels. To assess the risk for type 2 diabetes, we studied 220 patients and 596 normoglycemic control subjects. For myocardial infarction, 477 patients with evidence of myocardial infarction on electrocardiogram and 808 control subjects were studied. A 192-bp allele was present in 88% of the population, suggesting that this is the wild-type allele from which all other alleles originated. Body height was, on average, 2.7 cm lower (95% CI for difference -4.6 to -0.8 cm, P = 0.004), and serum IGF-I concentrations were 18% lower (95% CI for difference -6.0 to -1.3 mmol/l, P = 0.003) in subjects who did not carry the 192-bp allele. In noncarriers of the 192-bp allele, an increased relative risk for type 2 diabetes (1.7 95% CI 1.1-2.7) and for myocardial infarction (1.7 95% CI 1.1-2.5) was found. In patients with type 2 diabetes, the relative risk for myocardial infarction in subjects without the 192-bp allele was 3.4 (95% CI 1.1-11.3). Our study suggests that a genetically determined exposure to relatively low IGF-I levels is associated with an increased risk for type 2 diabetes and myocardial infarction.
Primary erythermalgia is a rare disorder characterized by recurrent attacks of red, warm, and painful hands and/or feet. The symptoms are generally refractory to treatment and persist throughout ...life. Five kindreds with multiple cases of primary erythermalgia were identified, and the largest was subjected to a genomewide search. We detected strong evidence for linkage of the primary erythermalgia locus to markers from chromosome 2q. The highest LOD score (
Z) was obtained with D2S2330 (
Z
max = 6.51). Analysis of recombination events identified D2S2370 and D2S1776 as flanking markers, on chromosome 2q31-32. This defines a critical interval of 7.94 cM that harbors the primary erythermalgia gene. Affected members within the additional families also shared a common haplotype on chromosome 2q31-32, supporting our linkage results. Identification of the primary erythermalgia gene will allow a better clinical classification of this pleomorphic group of disorders.
Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome ...scans have identified >18 other genomic regions that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in mapping susceptibility loci than in complex outbred populations. We describe a genome-wide search in a recently Dutch isolated population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a genome-wide scan using a combined linkage- and association-based approach. In addition to the HLA locus, evidence for type 1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and 17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved ancestral haplotype was found for chromosome 8q24.
We studied patients with idiopathic Parkinson's disease (PD) from an isolated population in the Netherlands aiming to map gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients ...were independently ascertained, of whom 62 presented late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor, indicating familiar clustering among the patients. This strong familial clustering was highly significant (P = 0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis (DISLAMB) revealed evidence of association at a nominal P-value < 0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found at a significance level of P < 0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q region. A significant association was found for marker D9S1838 (OR = 2.0, 95% CI 1.1-3.5, P = 0.014) and D14S65 (OR = 3.2, 95% CI 1.7-6.1, P < 0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q.
Triphalangeal thumb is a developmental anomaly, sometimes dominantly transmitted, characterized by a long, finger-like thumb with three phalanges instead of two. The underlying genetic defect is ...unknown, but presumably involves genes that regulate the differentiation of the developing forelimb. In two large kindreds with triphalangeal thumb, evidence for linkage to the long arm of chromosome 7 was obtained with a maximum lod score of 12.61. Multipoint linkage and haplotype analysis placed the gene close to the telomere of the long arm. To our knowledge this is the first time that a human gene involved solely in the pathologic morphogenesis of the hand and feet has been localized.
To study myocardial vascular development, stereological parameters were estimated in 24 Wistar rat hearts of six different age groups, from newborn to adult. The vascular surface density showed a ...sharp increase in the first 2 weeks, a peak around the age of 2 weeks, and then a steady decrease until it flattened in adulthood. In contrast, the vascular volume percentage, when plotted against age, decreased continuously with the greatest change in the first week, after which the curve flattened. These findings are compatible with an increase in the number of capillaries with a concomitant decrease of their diameters. Qualitative scrutiny of the histology did indeed support the idea that vessels become thinner. Reconstructions of the histological sections showed the same change three dimensionally. The reconstructions also demonstrated very small holes that seemed to go through the capillaries in the younger stages. Corrosion casts of the blood vessels were made using a casting resin. This was injected into the umbilical artery of rat embryos from 15 days gestation to birth. In postnatal rats of six age groups methacrylate was injected directly into the left ventricle. These casts supported the stereological data by showing an increase in number and decrease in diameter of capillaries, while during pre- and postnatal development, the intervascular spaces lengthened from small, irregular spaces to long, rectangular ones. Small holes, the probable precursors of such spaces, were clearly visible in the wider vessels of the youngest stages. All data point to an interesting mode of capillary growth, i.e. growth by division of existing vessels.
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