Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%--60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.

Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease.

A B S T R A C T A new human antigen is reported which is present only on blood neutrophils. A neutrophil-specific antigen, designated NAI, has previously been identified in two unrelated families, and was shown to be involved in fetomaternal incompatibility and the development of isoimmune neonatal neutropenia in five newborns. In the present paper, a second antigen, designated NB1, is identified in four families with seven affected children. Antibodies that react with this second antigen are shown to produce selective agglutination of neutrophils but not other blood cells. They are neither absorbed by cells prepared from solid tissues nor by non-neutrophilic blood cells.By family and population studies, NB is shown to be distinct from NA, representing an independent genetic locus. 68% of the New York population are homozygous for NB1, 29% heterozygous, and 3% negative. The NB locus is shown to be independent from those of HL-A and other known leukocyte antigens. No evidence for linkage between NA, NB, and red cell antigens was obtained.

This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Summary Mr. McLeod, the possessor of a new Kell phenotype, lacks antigenic determinants* K1 (Kell), K3 (Penney), and K5 (Peltz). He has variants of K2 (Cellano) and K4 (Rautenberg). This phenotype appears to establish K5 as distinct from K1, K2, K3, and K4. The notation used in this paper is one proposed for the purpose of testing the usefulness of a system of basically numerical symbols. Résumé Monsieur McLeod, qui possède un nouveau phénotype Kell, ne possède pas les déterminants antigéniques K 1, (Kell), K 3 (Penney) et K 5 (Peltz). Il a des variantes de K 2 (Cellano) et K 4 (Rautenberg). Ce phénotype semble établir que K 5 est différent de K 1, K 2, K 3 et K 4. La nomenclature utilisée dans cet article est proposée dans le but de déterminer l'utilité d'un système basé sur des symboles numériques. Zusammenfassung Herr McLeod verfügt über einen «neuen» Kell Phänotyp, dem folgende Antigendeterminanten fehlen: K 1 (Kell), K 3 (Penney) und K 5 (Peltz). Er weist Varianten von K 2 (Cellano) und K 4 (Rautenberg) auf. Dieser Phänotyp gestattet die Verschiedenheit von K 5 von K 1, K 2, K 3 und K 4 aufzuzeigen. Die in dieser Arbeit benützten Bezeichnungen dienten zur Prüfung der Brauchbarkeit einer auf Zahlenreihen beruhenden Terminologie.

In a previous report (1), a family with C2 deficiency in the homozygous and the heterozygous states was described. The propositus was of special interest because the complete absence of C2 was associated with some manifestations of systemic lupus erythematosus. Further studies of this family included analysis of possible genetic linkage of the deficiency with known genetic markers. Determinations of HL-A antigens provided evidence that linkage with this system was present. Methods and MaterialsSerum samples were obtained from clotted blood, quickly frozen, and stored at -60°C. Samples were thawed once. C2 determinations were performed by both hemolytic titration and radial immunodiffusion (1). The heterozygous individuals were recognized by their level of C2 which was close to one half the normal.HL-A typing was done on lymphocytes isolated from the peripheral blood by Ficoll-Isopaque gradient centrifugation. A two-stage microtoxicity assay procedure was used. 120 typing sera were used and 28 antigens were typed for. The typing sera were obtained from the New York Blood Center and the Transplantation Immunology Branch Serum Bank of NIAID (2). Unidirectional mixed leukocyte cultures (MLC) were performed according to Hartzman et al. (3). Briefly, lymphocytes were isolated by Ficoll-Hypaque gradient centrifugation. 3 × 106 X-irradiated (3,000 rad) stimulating cells and 1.5 × 105 in 0.2 ml of RPMI 1640 medium supplemented with streptomycin, penicillin, and 20% heat-inactivated normal human serum were mixed in the wells of Falcon microtiter plates (Falcon Plastics, Div. of BioQuest, Oxnard, Calif.). Each culture was set up in triplicate. After 6 days of incubation at 37°C in 5% CO2 humidified atmosphere, 2 ~Ci of [SH]thymidine was added to each culture 16 h before harvesting. The lymphocytes were harvested and processed for liquid scintillation counting. Results and DiscussionThe pedigree of the S family is depicted in Fig. 1. The propositus, II2, is a woman with manifestations of systemic lupus erythematosus and homozygous for C2 deficiency. HL-A analysis also indicated homozygosity for HL-A10,W18. This was checked in two laboratories with different typing sera. To verify this further, unidirectional MLC were carried out using her cells as the stimulator and those of her daughter as the responder. It was clear that her daughter's leukocytes did