Familial primary pulmonary hypertension is a rare autosomal dominant disorder that has reduced penetrance and that has been mapped to a 3-cM region on chromosome 2q33 (locus PPH1). The phenotype is characterized by monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles. These lesions lead to elevated pulmonary-artery pressures, right-ventricular failure, and death. Although primary pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs, including phentermine-fenfluramine. We genotyped 35 multiplex families with the disorder, using 27 microsatellite markers; we constructed disease haplotypes; and we looked for evidence of haplotype sharing across families, using the program TRANSMIT. Suggestive evidence of sharing was observed with markers GGAA19e07 and D2S307, and three nearby candidate genes were examined by denaturing high-performance liquid chromatography on individuals from 19 families. One of these genes (BMPR2), which encodes bone morphogenetic protein receptor type II, was found to contain five mutations that predict premature termination of the protein product and two missense mutations. These mutations were not observed in 196 control chromosomes. These findings indicate that the bone morphogenetic protein-signaling pathway is defective in patients with primary pulmonary hypertension and may implicate the pathway in the nonfamilial forms of the disease.

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We present the genomic sequence of Legionella pneumophila, the bacterial agent of Legionnaires' disease, a potentially fatal pneumonia acquired from aerosolized contaminated fresh water. The genome includes a 45-kilobase pair element that can exist in chromosomal and episomal forms, selective expansions of important gene families, genes for unexpected metabolic pathways, and previously unknown candidate virulence determinants. We highlight the genes that may account for Legionella's ability to survive in protozoa, mammalian macrophages, and inhospitable environmental niches and that may define new therapeutic targets.

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures 1 . Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances 2,3 . We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes ( Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.Correspondence should be addressed to R.O. (e-mail: ro6@columbia.edu). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2008 December 22. Published in final edited form as:Nat Genet. 2002 March ; 30(3): 335-341. doi:10.1038/ng832. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn 1995 we mapped the ADPEAF locus to a 10-cM region on chromosome 10q24 in a single extended pedigree 2 . Linkage was subsequently reported to an overlapping interval in another large family, narrowing the minimal genetic region to approximately 3 cM, assuming the causative gene was the same 4 . Analysis of additional pedigrees confirmed the linkage but failed to narrow the region further 5-7 . To screen for disease-related mutations, we resequenced all coding-exon and bordering-intron sequences from positional candidate genes in the overlap interval in one affected individual from each of three ADPEAF pedigrees showing linkage to chromosome 10q24 (families 6610, A and B; Fig. 2) 2,7 . We then genotyped putative diseaserelated mutations in all available family members from the three linked pedigrees, all family members from two smaller families with ADPEAF (families C and D; Fig. 2) and 123 unrelated control individuals.Resequencing of LGI1 identified presumptive mutations in each of the five families with ADPEAF (Table 1 and Fig. 2). All tested affected individuals from the five families harbored a single copy of a putative disease mutation, as did all obligate carriers and individuals classified as 'unknown' who were found to carry the disease-linked haplotype (Fig. 2). Several unaffected individuals also carried the disease haplotype and presumptive mutation. Whether these individuals manifest subclinical signs of disease or have undergone recent changes in affection status is not yet known, but the results are consistent with our previous estimate of 71% disease-gene penetrance in family 6610 (ref.2).To di...