Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene

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.     

Delineation of the critical interval for the familial exudative vitreoretinopathy gene by linkage and haplotype analysis

Familial exudative vitreoretinopathy (FEVR) is an ocular disorder characterized by deficient vascularization of the peripheral retina and causes visual loss attributable to various types of retinal detachment. The locus of the gene responsible for the autosomal dominant form of FEVR (EVR1) has been assigned to 11q13-23. However, a detailed evaluation of the critical region has not been made. We present the results of linkage analysis of the EVR1 locus on 11q13-23 in 43 individuals belonging to seven unrelated families of Japanese origin. Multipoint analysis has shown that six families out of the seven are linked with 11q13-23 markers. Haplotype analysis reveals that the putative region is probably flanked by polymorphic markers D11S1362 and CHLC.GATA30G01, which are approximately 200 kb apart, although the recombination events in small families such as presented in this study should be interpreted cautiously.     

Localization of the familial Mediterranean fever gene (FMF) to a 250-kb interval in non-Ashkenazi Jewish founder haplotypes. The French FMF Consortium.

Chromosome 16p13.3 harbors a gene (MEF) associated with familial Mediterranean fever (FMF), a recessive disease very common in populations of Mediterranean ancestry. In the course of positional cloning of MEF, we genotyped 26 non-Ashkenazi Jewish FMF pedigrees (310 meioses) with 15 microsatellite markers, most of which were recently developed by Généthon. Identification of recombination events in the haplotypes allowed narrowing of the MEF interval to a region between D16S3124 (telomeric) and D16S475 (centromeric). Two markers, D16S3070 and D16S3275, a microsatellite marker isolated from a YAC that also contains D16S3070, showed no recombination with the disease. Linkage disequilibrium and haplotype analysis highlighted the existence of a founder haplotype in our population. The core ancestral alleles were present in 71% of MEF-bearing chromosomes at loci D16S3070 and D16S3275. Furthermore, identification of historical crossing-over events in these pedigrees indicated that MEF is located between these two loci, which are both contained in a 250-kb genomic fragment.     

A linkage and physical map of chromosome 22, and some applications to gene mapping.

A genetic map of human chromosome 22 has been derived from physical assignments and multilocus linkage analysis. It consists of the loci for the immunoglobulin lambda light-chain variable (IGLV) and immunoglobulin lambda light-chain constant (IGLC) regions, myoglobin (MB), the sis proto-oncogene (SIS), and an arbitrary probe (D22S1). The first RFLPs at the loci for SIS, IGLV, and MB are described. The most likely gene order on the basis of multilocus analysis was cen-(IGLV-IGLC)-D22S1-MB-SIS. This map provides further evidence for localization of the P1 polymorphism of the P blood group to chromosome 22, close to the SIS locus. Analysis of families segregating recessive congenital methemoglobinemia (RCM), a disease in which the cytochrome b5 reductase is defective, as well as of families with cases of hereditary low levels of cytochrome b5 reductase activity, confirmed that the locus responsible for RCM is on chromosome 22. Biochemical studies had already suggested that mutation at the cytochrome b5 reductase locus (DIA1) is responsible for RCM. We found no evidence of genetic heterogeneity between the families segregating RCM and the families exhibiting cases of low cytochrome b5 reductase activity. Linkage analysis indicated that the most probable location of DIA1 lies between MB and SIS.     

MapGene2Chrom基于Perl和SVG语言绘制基因物理图谱

遗传图谱表现形式简洁明了,为分析遗传规律、克隆基因提供了便利。Gbrowse、MapViewer等工具虽然能够协助研究人员绘制相似形式的物理图谱,但有很大的局限性:(1)数据需提前布置好;(2)输出结果无法灵活修改。鉴于此,文章基于Perl和SVG语言,开发了一款生物辅助作图软件MapGene2Chrom的本地版与网页版,该软件能够依据输入数据快速绘制相应的物理图谱。该软件输入数据格式简单,输出结果易于修改,图片格式为SVG矢量图,具有很好的移植性,以期为研究人员绘制物理图谱提供便利。     

A genetic and physical map of the region containing PLASTOCHRON1, a heterochronic gene,in rice ( Oryza sativa L.)

The rice heterochronic gene plastochron1, pla1, shows shorter plastochron and ectopic expression of the vegetative program during the rice reproductive phase resulting in aberrant panicle formation. A genetic and physical map was constructed to isolate the causal gene for the pla1 syndrome. Small-scale mapping was carried out to determine the approximate map position of the pla1 locus, and then a high-resolution genetic map was made for pla1-1, one of the pla1 alleles, using an F₂ population comprising 578 pla1-1 homozygous plants. In a high-resolution genetic map, the pla1-1 locus was found to map between RFLP markers C961 and R1738A on chromosome 10, within a 3.6-cM genetic distance. A physical map encompassing the pla1-1 locus was constructed by overlapping Bacterial Artificial Chromosome (BAC) clones through chromosome walking. PCR-based RFLP markers from BAC-end clones were developed and mapped relative to the pla1 locus. Physical map construction using BAC clones indicated that a BAC clone, B44A10 (167-kb), contained the pla1 locus within 74-kb corresponding to a 0.52-cM genetic distance. Gene prediction of 74-kb region carrying the pla1 locus suggested several candidate genes for the pla1 gene. Identification of a candidate gene for pla1 will be made by sequence analysis of allele variation and cDNA screening.     

ACE gene and physical activity, blood pressure, and hypertension: a population study in Finland.

The study evaluated the association of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene (ACE I/D) with self-reported moderate-intensity leisure time physical activity (MILTPA), arterial blood pressure (BP) and history of hypertension (HT). A representative population-based sample of 721 middle-aged adults (358 women) from two areas of Finland was genotyped for the ACE I/D. After exclusion criteria were applied, 455 subjects (288 women) were selected for the analysis. The distribution of the ACE I/D genotypes did not differ significantly among frequent vs. nonfrequent MILTPA groups (chi(2) = 2.556; df = 2; P value = 0.279). The main predictors of BP were male gender, age, body mass index, and arterial pulse. Additionally, tobacco smoking and alcohol consumption also had a significant main effect on diastolic BP. HT was significantly more frequent in subjects with obesity, family history of cardiovascular disease, or lower educational level. As for BP, neither ACE I/D nor MILTPA was associated with HT. The study confirmed recent reports from population-based studies of no association between ACE I/D and physical fitness. The study also confirmed a lack of association between ACE I/D and BP or HT.     

Chromosome no. 1 of man and chimpanzee: identity of gene mapping for three loci: PPH, PGM1, and Pep-C.

Cytogenetic and biochemical analysis of 10 independant Chimpanzee-Mouse cell hybrids and of 18 subclones of one of these showed that PPH, PGM1 and Pep-C are localized on the Chimpanzee chromosome homologous to the human chromosome No. 1.     

The gene for the ataxia-telangiectasia variant,Nijmegen breakage syndrome,maps to a 1-cM interval on chromosome 8q21.

Nijmegen breakage syndrome (NBS; Seemanová II syndrome) and Berlin breakage syndrome (BBS), also known as ataxia-telangiectasia variants, are two clinically indistinguishable autosomal recessive familial cancer syndromes that share with ataxia-telangiectasia similar cellular, immunological, and chromosomal but not clinical findings. Classification in NBS and BBS was based on complementation of their hypersensitivity to ionizing radiation in cell-fusion experiments. Recent investigations have questioned the former classification into two different disease entities, suggesting that NBS/BBS is caused by mutations in a single radiosensitivity gene. We now have performed a whole-genome screen in 14 NBS/BBS families and have localized the gene for NBS/BBS to a 1-cM interval on chromosome 8q21, between markers D8S271 and D8S270, with a peak LOD score of 6.86 at D8S1811. This marker also shows strong allelic association to both Slavic NBS and German BBS patients, suggesting the existence of one major mutation of Slavic origin. Since the same allele is seen in both former complementation groups, genetic homogeneity of NBS/BBS can be considered as proved.