5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations.

• MeSH
• aktivace enzymů MeSH
• alely MeSH
• alternativní sestřih MeSH
• exony MeSH
• fibroblasty metabolismus   MeSH
• genetické asociační studie * MeSH
• homocystinurie diagnóza   genetika   metabolismus   MeSH
• introny MeSH
• jednonukleotidový polymorfismus MeSH
• kinetika MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   genetika   metabolismus   MeSH
• mutace MeSH
• psychotické poruchy diagnóza   genetika   metabolismus   MeSH
• stabilita proteinů MeSH
• svalová spasticita diagnóza   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects <1 year of age experienced lower risk of sequence type 11 (ST-11) cc, ST-32 cc, and ST-269 cc disease and higher risk of disease due to unassigned STs, 1- to 4-year-olds experienced lower risk of ST-11 cc and ST-32 cc disease, 5- to 14-year-olds were less likely to experience ST-11 cc and ST-269 cc disease, and ≥25-year-olds were more likely to experience disease due to less common ccs and unassigned STs. Younger and older subjects were vulnerable to a more diverse set of genotypes, indicating the more clonal nature of genotypes affecting adolescents and young adults. Knowledge of temporal and spatial diversity and the dynamics of meningococcal populations is essential for disease control by vaccines, as coverage is lineage specific. The nonrandom age distribution of hyperinvasive lineages has consequences for the design and implementation of vaccines, as different variants, or perhaps targets, may be required for different age groups.

• MeSH
• antigeny bakteriální imunologie   MeSH
• bakteriální pouzdra imunologie   MeSH
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• meningokoková meningitida imunologie   mikrobiologie   prevence a kontrola   MeSH
• meningokokové vakcíny imunologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• multilokusová sekvenční typizace MeSH
• Neisseria meningitidis séroskupiny B imunologie   MeSH
• Neisseria meningitidis imunologie   izolace a purifikace   MeSH
• předškolní dítě MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• věkové rozložení MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Rye (Secale cereale L.) is an exceptionally climate-resilient cereal crop, used extensively to produce improved wheat varieties via introgressive hybridization and possessing the entire repertoire of genes necessary to enable hybrid breeding. Rye is allogamous and only recently domesticated, thus giving cultivated ryes access to a diverse and exploitable wild gene pool. To further enhance the agronomic potential of rye, we produced a chromosome-scale annotated assembly of the 7.9-gigabase rye genome and extensively validated its quality by using a suite of molecular genetic resources. We demonstrate applications of this resource with a broad range of investigations. We present findings on cultivated rye's incomplete genetic isolation from wild relatives, mechanisms of genome structural evolution, pathogen resistance, low-temperature tolerance, fertility control systems for hybrid breeding and the yield benefits of rye-wheat introgressions.

• MeSH
• fyziologická adaptace genetika   MeSH
• fyziologický stres MeSH
• genom rostlinný * MeSH
• genová introgrese MeSH
• imunita rostlin genetika   MeSH
• karyotyp MeSH
• mapování chromozomů metody   MeSH
• pšenice genetika   MeSH
• regulace genové exprese u rostlin MeSH
• rostlinné proteiny genetika   metabolismus   MeSH
• šlechtění rostlin metody   MeSH
• zemědělské plodiny genetika   imunologie   MeSH
• žito genetika   imunologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH