Rhesus factor polymorphism has been an evolutionary enigma since its discovery in 1939. Carriers of the rarer allele should be eliminated by selection against Rhesus positive children born to Rhesus negative mothers. Here I used an ecologic regression study to test the hypothesis that Rhesus factor polymorphism is stabilized by heterozygote advantage. The study was performed in 65 countries for which the frequencies of RhD phenotypes and specific disease burden data were available. I performed multiple multivariate covariance analysis with five potential confounding variables: GDP, latitude (distance from the equator), humidity, medical care expenditure per capita and frequencies of smokers. The results showed that the burden associated with many diseases correlated with the frequencies of particular Rhesus genotypes in a country and that the direction of the relation was nearly always the opposite for the frequency of Rhesus negative homozygotes and that of Rhesus positive heterozygotes. On the population level, a Rhesus-negativity-associated burden could be compensated for by the heterozygote advantage, but for Rhesus negative subjects this burden represents a serious problem.

• MeSH
• Child MeSH
• Gene Frequency MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Heterozygote MeSH
• Homozygote MeSH
• Rh-Hr Blood-Group System genetics   MeSH
• Humans MeSH
• Survival Rate MeSH
• Polymorphism, Genetic * MeSH
• Regression Analysis MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Arginine therapeutic use   MeSH
• Child MeSH
• Heterozygote MeSH
• Carnitine therapeutic use   MeSH
• Infant MeSH
• Humans MeSH
• Diet, Protein-Restricted MeSH
• Ornithine Carbamoyltransferase physiology   MeSH
• Amino Acid Metabolism, Inborn Errors diet therapy   enzymology   drug therapy   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

• MeSH
• Genetic Carrier Screening methods   MeSH
• Genetics, Medical MeSH
• Humans MeSH
• Check Tag
• Humans MeSH

U 63leté ženy s klinickou diagnózou hypertenze, aterosklerózy koronárních a končetinových tepen, trombembo- lismu do cévního mozkového řečiště a převodní poruchy srdeční bylo při sekci jako další nález prokázáno lysozomální střádání identifikované histochemickou a elektronoptickou analýzou spolu s chromatografií lipidů jako Fabryho nemoc. Střádanými lipidy byly především neutrální glykosfingolipidy ze série globo- (globotriaosylceramid) a série gala- (galabiosylceramid), které se hromadí v důsledku nedostatečné aktivity degradačního enzymu alfa- galaktosi- dázy A. Výrazné střádání těchto specifických lipidů bylo přítomno v kardiomyocytech, v hladké svalovině medie arterií (srdce, ledviny, játra, slezina, plíce) v podocytech a mezangiálních buňkách renálních glomerulů, v epiteliích Henleovy kličky a distálních tubulů. V cévním endotelu bylo střádání na hranici zjistitelnosti. Střádání nevedlo k prokazatelným orgánovým poruchám s výjimkou srdce, kde se nepochybně významně podílelo na hypertrofii svaloviny. Vyšetřením rodinných příslušníků byla zjištěna u syna pacientky (stáří 41 let) kombinace renálních, kardiálních a kožních změn příznačných pro Fabryho nemoc, která však nebyla klinicky diagnostikována. Diagnózu potvrdil průkaz deficitu alfa-galaktosidázy A v periferních leukocytech a bodové mutace L293X v VI. exonu příslušného genu. U vnučky (stáří 15 let) byl prokázán biochemicky i molekulárně geneticky heterozygotní stav Fabryho nemoci v preklinickém stadiu.

The authors detected on necropsy in a 63-year-old woman with the clinical diagnosis of hypertension, atheroscle- rosis of the coronary and peripheral arteries, thromboembolism into the cerebral circulation and impaired cardiac conductivity lysosomal storage identified by histochemical and electronoptic analyses along with lipid chromatog- raphy as Fabry's disease. The stored lipids were neutral glycosphingolipids of the globo series globotriaosylceramide) and of the gala- series (galabiosylceramide) which accumulated as a result of deficient activity of the degrading enzyme alpha galactosidase A. Marked accumulation of these specific lipids was found in cardiomyocytes, in smooth muscles (of the media in arteries of the heart, kidneys, liver, spleen, lungs) in podocytes and mesangial cells of renal glomeruli, in epithelia of Henle's loop and in the distal tubules. In the vascular endothelium the storage was at the borderline of detectability. Accumulation did not lead to detectable organ disorders with the exception of the heart where it participated, no doubt, significantly in the cardiocyte hypertrophy. Examination of relatives revealed in the proband's son (age 41 years) a combination of renal, cardiac and skin changes typical for Fabry's disease which, however was not clinically diagnosed. The diagnosis was confirmed by proving of alpha-galactosidase A deficiency in the peripheral leucocytes and point mutation L293X in the VIth exon of the appropriate gene. In a granddaughter (age 15 years) biochemical and molecular genetic methods revealed the heterozygous state of Fabry's disease in preclinical stage.

• MeSH
• alpha-Galactosidase MeSH
• Genetic Carrier Screening MeSH
• Fabry Disease genetics   mortality   MeSH
• Cardiomyopathies diagnosis   therapy   MeSH
• Middle Aged MeSH
• Humans MeSH
• Autopsy MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Danon disease (DD) is an X-linked disorder caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene (Xq24). DD is characterized by cognitive deficit, myopathy, and cardiomyopathy in male patients. The phenotype is variable and mitigated in females. The timely identification of de-novo LAMP2 mutated family members, many of whom are heterozygous females, remains critical for their treatment and family counseling. DD laboratory testing builds on minimally invasive quantification of the LAMP2 protein in white blood cells and characterization of the specific mutation. This integrative approach is particularly helpful when assessing suspect female heterozygotes. LAMP2 exon-copy number variations (eCNVs) were so far reported only in X-hemizygous male DD probands. In heterozygous female DD probands, the wild-type allele may hamper the identification of an eCNV even if it results in the complete abolition of LAMP2 transcription and/or translation. To document the likely underappreciated rate of occurrence and point out numerous potential pitfalls of detection of the LAMP2 eCNVs, we present the first two DD heterozygote female probands who harbor novel multi-exon LAMP2 deletions. Critical for counseling and recurrence prediction, we also highlight the need to search for somatic-germinal mosaicism in DD families.

• MeSH
• Child MeSH
• Adult MeSH
• Exons genetics   MeSH
• Glycogen Storage Disease Type IIb genetics   MeSH
• Heterozygote MeSH
• Humans MeSH
• Lysosomal-Associated Membrane Protein 2 genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Family MeSH
• Pedigree MeSH
• Base Sequence MeSH
• DNA Copy Number Variations genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Východisko. Autozomálně recesivně dědičný syndrom chromozomální instability Nijmegen breakage syndrom (NBS) způsobený mutací v NBS1 genu na 8q21 je spojen s vysokým výskytem lymforetikulárních malignit v důsledku poruchy reparace DNA (double strand breaks). Ve slovanské populaci je většina pacientů homozygoty tzv. „slovanské mutace“ 657del5 v exonu 6. Zvýšený výskyt maligních solidních tumorů v rodinách pacientů s NBS byl popsán již před identifikací odpovědného genu a zvýšené riziko malignit heterozygotů bylo tak hypotetické. Možnost odlišit v rodinách nositele mutace a normální homozygoty dovoluje tuto hypotézu ověřit. Metody a výsledky. Molekulárně genetickým vyšetřením prarodičů a prvostupňových příbuzných se nám nyní ve 28 rodinách našich 39 pacientů podařilo stanovit genotyp 79 ze 112 prarodičů a 54 jejich rodičů a sourozenců. Jediná rodina měla postižené děti v důsledku compound heterozygosity mutace 657del5 a mutace R215W ve stejném exonu NBS1 genu. Rodiny byly vyšetřovány genealogicky tak, aby byla získána data o příbuzných probanda ve 4 generacích. Anamnesticky získané údaje byly opakovaně doplňovány a objektivně ověřovány v matrikách a zdravotní dokumentaci. Sedm rodin je sledováno 20–30 let, 6 rodin 10–20 let a 15 rodin 1–10 let. Z 28 rodin se u obojích prarodičů podařilo vyšetřit genotyp v 18 rodinách, přičemž jednou byla zjištěna non-paternita a jednou mutace R215W, v 5 rodinách jen u jedněch prarodičů, v 5 rodinách se nepodařilo stanovit genotyp žádného z prarodičů. Mezi 40 prarodiči – normálními homozygoty se vyskytla malignita u 3 (7,4 %), zatímco mezi 39 heterozygoty mutace 657del5 v NBS1genu byl výskyt malignit dokumentován u 15 (38,2 %). Průměrný věk manifestace malignity ve skupině heterozygotů byl 59,3 let (rozptyl 47–72 let), ve skupině homozygotů 52,6 let (rozptyl 44–62 let). Devět prarodičů zemřelo na malignitu před objevením NBS1 genu a jejich genotyp byl odvozen u 7 genealogicky na základě genotypu manželky a dětí, u dvou ze zachované DNA. Z nich od 3 na malignitu zemřelých prarodičů se podařilo získat nádorovou tkáň pro molekulárně genetické vyšetření, cílené na LOH či amplifikaci NBS1 genu. U dalších 5 prarodičů – heterozygotů se malignita manifestovala až po stanovení genotypu molekulárně genetickým vyšetřením a následně také od 3 nádorová tkáň byla získána pro molekulárně genetické vyšetření. Závěry. Věkové rozložení i socioekonomický status obou skupin prarodičů se nelišil, poměr pohlaví byl lehce posunut ve prospěch ženského pohlaví ve skupině prarodičů homozygotů (22 žen a 18 mužů) a ve skupině heterozygotů ve prospěch mužského pohlaví (21 mužů a 18 žen). Poměr pohlaví mezi heterozygotními prarodiči s malignitou byl rovněž posunut ve prospěch mužského pohlaví (11 mužů a 4 ženy), ve skupině prarodičů homozygotů byly malignitou postiženy 2 ženy a 1 muž. Ze zdravotnické a matriční dokumentace ověřený výskyt malignit byl významně častější mezi prarodiči heterozygoty mutace NBS1 genu než mezi zdravými homozygoty. Také mezi sourozenci a rodiči prarodičů byl rozdíl ve frekvenci malignit u heterozygotů signifikantně vyšší (5 z 18, tj. 27,7 %) oproti frekvenci malignit u zdravých homozygotů (2 z 36, tj. 5,5 %).

Background. The autosomal recessive chromosomal instability and hyperradiosensitivity Nijmegen breakage syndrome (NBS) in consequence of a mutation in the NBS1 gene at 8q21 is associated with high occurrence of lymphoreticular malignancies due to deficient DNA reparation (double strand breaks). In the Slavic population the majority of patients are homozygotes of the so-called “Slavic mutation” 657del5 in exon 6. Increased occurrence of malignant solid tumors (1) in families of NBS patients has been described already prior to the identification of the responsible gene, and the increased risk of malignancies in heterozygotes was thus hypothetical. Methods and Results. The possibility of discerning mutation carriers in families from normal homozygotes enables verification of that hypothesis. Through molecular genetics investigations of grandparents and immediate relatives, we have been successful in determining the genotype in 79 of 112 grandparents in 28 families of our 39 patients and 54 their parents and siblings. A single family had affected children in consequence of compound heterozygosity of the 657del5 and R215W mutations in the same exon of the NBS1 gene. The proband’s families were investigated genealogically and data on relatives were obtained over four generations. Obtained data were repeatedly supplemented and objectively verified in church books and in healthcare documentation. Seven families have been followed up for 20–30 years, six families for 10–20 years, and 15 families for 1–10 years. Out of 28 families we were successful in examining the genotype of both grandparents in 18 families, there having been revealed one non-paternity; in five families only one genetickéof the grandparents has been examined; in five families we were not successful in examining any grandparent. Among 40 grandparents – normal homozygotes, there has appeared a malignancy in three (7.4 %), while among 39 heterozygotes of mutation 657del5 in the NBS1 gene malignancies were documented in 15 (38,2 %). Mean age of NBS heterozygotes at manifestation of malignancy was 59.3 year (range 47–72 years), in the group of homozygotes it was 52.6 years (range 44–62 years). Nine grandparents died of malignancy prior to the discovery of the NBS1 gene and their genotype has been deduced genealogically in seven on the basis of the genotype in the sponse and children, in two from preserved DNA. Out of that number, from three grandparents that had died of malignancies we were successful in obtaining neoplastic tissue for molecular genetics investigation, aimed at LOH or amplification of the NBS1 gene. In another seven grandparents – heterozygotes, malignancies were manifested after determination of their genotype by DNA analysis, and consequently also from tumor tissue that has been obtained from three of them for molecular genetic investigation. Conclusions. The age distribution and socio-economic status of both groups of grandparents did not differ, the sex ratio was slightly shifted towards females in the group of homozygotic grandparents (22 females and 18 males), and in the group of heterozygotes it was towards males (21 males and 18 females). The sex ratio between heterozygotic grandparents with malignancies was likewise shifted towards the male gender (11 males and 4 females), in the group of homozygotic grandparents malignancy affected one male and two females. As verified in healthcare and church books documentation, the occurrence of malignancies was significantly more frequent among grandparents heterozygotic for NBS1 mutation than in healthy homozygotes. Among sibs of grandparents and great-grandparents was found significant difference in frequency of malignancies in heterozygotes (5/18 = 27,7 %) and healthy homozygotes (2/36 = 5,5 %), too.

• MeSH
• Genetic Carrier Screening MeSH
• Molecular Diagnostic Techniques MeSH
• DNA analysis   MeSH
• Research Support as Topic MeSH
• Genetic Diseases, Inborn diagnosis   genetics   mortality   MeSH
• Genotype MeSH
• Homozygote MeSH
• Humans MeSH
• Neoplasms diagnosis   genetics   MeSH
• Family MeSH
• Check Tag
• Humans MeSH

• MeSH
• Erythrocytes, Abnormal metabolism   MeSH
• Chromosome Deletion MeSH
• Adult MeSH
• Globins genetics   MeSH
• Hemoglobins metabolism   MeSH
• Heterozygote MeSH
• Humans MeSH
• Thalassemia genetics   blood   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

• MeSH
• Phenotype MeSH
• Karyotyping MeSH
• Pedigree MeSH
• Check Tag
• Female MeSH

Chromosome pairing in meiosis usually starts in the vicinity of the telomere attachment to the nuclear membrane and congregation of telomeres in the leptotene bouquet is believed responsible for bringing homologue pairs together. In a heterozygote for an inversion of a rye (Secale cereale L.) chromosome arm in wheat, a distal segment of the normal homologue is capable of chiasmate pairing with its counterpart in the inverted arm, located near the centromere. Using 3D imaging confocal microscopy, we observed that some telomeres failed to be incorporated into the bouquet and occupied various positions throughout the entire volume of the nucleus, including the centromere pole. Rye telomeres appeared ca. 21 times more likely to fail to be included in the telomere bouquet than wheat telomeres. The frequency of the out-of-bouquet rye telomere position in leptotene was virtually identical to the frequency of telomeres deviating from Rabl's orientation in the nuclei of somatic cells, and was similar to the frequency of synapsis of the normal and inverted chromosome arms, but lower than the MI pairing frequency of segments of these two arms normally positioned across the volume of the nucleus. Out-of-position placement of the rye telomeres may be responsible for reduced MI pairing of rye chromosomes in hybrids with wheat and their disproportionate contribution to aneuploidy, but appears responsible for initiating chiasmate pairing of distantly positioned segments of homology in an inversion heterozygote.

• MeSH
• Cell Nucleus genetics   ultrastructure   MeSH
• Centromere chemistry   ultrastructure   MeSH
• Chimera genetics   MeSH
• Chromosome Inversion * MeSH
• Chromosomes, Plant chemistry   ultrastructure   MeSH
• Species Specificity MeSH
• Heterozygote MeSH
• In Situ Hybridization, Fluorescence MeSH
• Microscopy, Confocal MeSH
• Chromosome Pairing MeSH
• Image Processing, Computer-Assisted statistics & numerical data   MeSH
• Meiotic Prophase I * MeSH
• Triticum genetics   ultrastructure   MeSH
• Plant Cells metabolism   ultrastructure   MeSH
• Telomere chemistry   ultrastructure   MeSH
• Secale genetics   ultrastructure   MeSH
• Imaging, Three-Dimensional methods   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Cíl studie: Leukemický inhibiční faktor (LIF) je jedním z klíčových cytokinů embryo-maternálního molekulárního dialogu, který probíhá během implantace embrya. Naším cílem bylo zjistit prevalenci mutací v genu pro LIF v populaci neplodných žen a sledovat jejich vliv na úspěšnost léčby. Typ studie: Kohortová studie. Název a sídlo pracoviště: Gynekologicko-porodnická klinika LF UK a FN v Plzni. Metodika a soubor: Vyšetřili jsme 399 infertilních a 202 kontrolních zdravých plodných žen. K analýze jsme použili elektroforézu probíhající v teplotním gradientu (TGGE) s následnou sekvenací všech TGGE pozitivních vzorků. Statistické zhodnocení rozdílu mezi skupinou neplodných pacientek a skupinou fertilních kontrol bylo provedeno pomocí Fisherova exaktního testu pro čtyřpolní tabulky. Výsledky: Ve skupině neplodných žen byla u 12 z nich detekována potenciálně funkční mutace v genu pro LIF, bodová záměna G za A na pozici 3400. Tato mutace vede k výměně valinu za methionin v 64. kodónu (V64M). V kontrolní skupině zdravých plodných žen nebyla žádná mutace nalezena, což znamená, že výskyt mutací v genu pro LIF je signifikantně zvýšen v populaci neplodných v porovnání s kontrolní skupinou (p=0,01, Fisherův exaktní test pro čtyřpolní tabulky). Sedm z těchto žen po léčbě otěhotnělo. Závěr: Výsledky prokazují, že mutace v genu pro LIF na pozici 3400 snižuje plodnost, ale její výskyt neznamená, že žena nebude moci být úspěšně léčena pomocí běžných metod léčby neplodnosti. Ačkoliv se mutace v genu pro LIF vyskytují vzácně, jejich vliv na molekulární pochody během implantace a časné embryogeneze by měl být objasněn.

Objective: The leukemia inhibitory factor (LIF) is one of the most important signaling factors in the embryo-maternal cross talk during the embryo implantation. We investigated the prevalence of the LIF gene mutations in the population of infertile women and their impact on infertility treatment. Design: A cohort study. Setting: Department of Obstetrics and Gynecology, Faculty of Medicine and University Hospital of Charles University, Pilsen. Subjects and methods: The population to screen consisted of 399 infertile women. The control population was comprised of 202 healthy fertile subjects. For the mutational analysis, the temperature gradient gel electrophoresis (TGGE) followed by subsequent sequencing of the positive samples, had been used. The groups of fertile controls and infertile patients were compared for statistically significant difference using the Fisher’s 2 by 2 Exact test. Results: Twelve potentially functional LIF gene mutations, the G to A transversion at the position 3400 leading to the valin to methionin exchange at codon 64 (V64M) were detected in the group of infertile women. No mutations were identified in the control group, which means that the frequency of functionally relevant mutations of the LIF gene in infertile women is significantly enhanced in comparison with controls (P = 0.01, Fisher’s 2 by 2 Exact test ). Seven of these patients were successfully treated by in vitro fertilization (IVF). Conclusion: The results suggest that the LIF gene mutation, the heterozygote G to A transition on the position 3400, affects fertility but the infertility treatment can succeed. Even though LIF gene mutations occur infrequently and can be overcome by infertility treatment, their impact on molecular events during early phases of pregnancy should be further elucidated.

• MeSH
• Research Support as Topic MeSH
• Embryo Implantation genetics   MeSH
• Leukemia Inhibitory Factor physiology   genetics   MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Infertility, Female etiology   genetics   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Comparative Study MeSH