Adipocyte-derived leucine aminopeptidase (ALAP) inactivates angiotensin II and/or generates bradykinin in the kidney, suggesting a possible role for ALAP in the regulation of blood pressure. We considered the hypothesis that genomic variants of the ALAP gene are associated with hypertension or individual variations in blood pressure. We screened for mutations in the ALAP gene in 48 unrelated Japanese individuals and identified 33 polymorphisms including 15 novel polymorphisms. We then performed a two-stage analysis. In the first stage, the eight missense polymorphisms were evaluated for associations with blood pressure in 96 apparently healthy individuals. In the second stage, only the most promising polymorphisms were evaluated for association with essential hypertension in 143 hypertensive and 348 normotensive subjects. Among the eight missense polymorphisms, the Ile276Met and Lys528Arg polymorphisms showed significant association with blood pressure. Subsequent analysis confirmed association between the Lys528Arg polymorphism and essential hypertension. The estimated odds ratio for essential hypertension was 2.3 for presence of the Arg allele at codon 528, in comparison with presence of the Lys/Lys genotype (P = 0.004). These findings support involvement of ALAP in the regulation of blood pressure.

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A naturally occurring mutation of the mass1 (monogenic audiogenic seizure-susceptible) gene recently has been reported in the Frings mouse strain, which is prone to audiogenic seizures. The human orthologous gene, MASS1, was mapped to chromosome 5q14, for which we previously have reported significant evidence of linkage to febrile seizures (FEB4). We screened for MASS1 mutations in individuals from 48 families with familial febrile seizures and found 25 DNA alterations. None of nine missense polymorphic alleles was significantly associated with febrile seizures; however, a nonsense mutation (S2652X) causing a deletion of the C-terminal 126 amino acid residues was identified in one family with febrile and afebrile seizures. Our results suggest that a loss-of-function mutation in MASS1 might be responsible for the seizure phenotypes, though it is not likely that MASS1 contributed to the cause of febrile seizures in most of our families.

Febrile seizures (FSs) represent the most common form of childhood seizure. In the Japanese population, the incidence rate is as high as 7%. It has been recognized that there is a significant genetic component for susceptibility to this type of seizure. Two putative FS loci, FEB1 (chromosome 8q13-q21) and FEB2 (chromosome 19p), have been mapped. Furthermore, a mutation in the voltage-gated sodium (Na(+))-channel beta1 subunit gene ( SCN1B ) at chromosome 19q13.1 was identified in a family with a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS(+)). These loci are linked to some large families. In this study, we conducted a genome-wide linkage search for FS in one large family with subsequent linkage confirmation in 39 nuclear families. Significant linkage was found at D5S644 by multipoint non-parametric analysis using GENEHUNTER ( P = 5.4 x 10(-6)). Estimated lambda(s)at D5S644 was 2.5 according to maximum likelihood analysis. Significant linkage disequilibria with FS were observed at the markers D5S644, D5S652 and D5S2079 in 47 families by transmission disequilibrium tests. These findings indicate that there is a gene on chromosome 5q14-q15 that confers susceptibility to FSs and we call this gene FEB4.

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Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder.Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33-q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neurotransmitter release in response to stress and other precipitating factors. IntroductionThe paroxysmal dyskinesias consist of clinically and genetically distinct phenotypes, including paroxysmal kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and paroxysmal nonkinesigenic dyskinesia (PNKD) (1, 2). PNKD is a highly penetrant autosomal dominant disorder in which individuals have 1- to 4-hour attacks consisting of dystonia and choreoathetosis (3). These attacks can be induced reliably by administration of caffeine or alcohol and frequently when patients are stressed. The causative gene was mapped to chromosome 2q33-q35 (4, 5), and mutations in the PNKD gene (formerly called MR-1) were subsequently identified in PNKD families (6)(7)(8)(9)(10).The PNKD gene has at least 3 alternate splice forms, which encode proteins of 385, 361, and 142 amino acids. The long isoform of PNKD (PNKD-L) is specifically expressed in CNS, while the medium isoform (PNKD-M) and short isoform (PNKD-S) are ubiquitously expressed (7). Two missense mutations (Ala to Val) located at amino acids 7 or 9 of PNKD-L and PNKD-S were found in most patients, and a third mutation (Ala to Pro) at position 33 was reported in 1 family (11). Both PNKD-L and PNKD-M have a putative catalytic domain that is homologous to hydroxyacylglutathione hydrolase (HAGH), a member of the zinc metallo-hydrolase enzyme family, which contains β-lactamase domains. HAGH functions in a pathway to detoxify methylglyoxal, a by-product of oxidative stress (12). The normal role of PNKD in cells and the contribution of mutations to pathophysiology of PNKD are not known.Dyskinesia is seen with many genetic and acquired disorders of the brain. Theoretically, such hyperkinetic movements could have their genesis in the basal ganglia, the cerebellum, or even in the cortex. Having cloned the gene and shown by in situ hybridization that it is...

The authors found a novel locus on chromosome 18p11.2 for febrile seizures (FSs). IMPA2 is likely to be an FS susceptibility gene.

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