Typical Families Research Articles

Remarks on the BOADICEA model of genetic susceptibility to breast and ovarian cancer

Sir, With much interest we read the paper by Antoniou and colleagues (British Journal of Cancer, October 18, p 1580). These researchers described the development of a genetic model for familial breast cancer, named BOADICEA, which takes into account the simultaneous effects of BRCA1, BRCA2 and other genes. There is a considerable need for such predictions for purposes of management of women referred to genetic clinics and for the considerations of eligibility of any prophylactic interventions in both the clinical and research settings. The BOADICEA model requires a computer program for risk estimation, which is not easy to use in clinical practice. Moreover, such a model is mostly hard to understand for clinicians. Understandable risk estimation should, however, be available to clinicians, so that they know what they are actually doing while estimating disease risks. Our concern about this aspect of the BOADICEA model was illustrated in Figure 3. The authors presented a woman aged 40 years and unaffected with cancer. Her mother and maternal aunt developed ovarian cancer and two other maternal aunts developed breast cancer before the age of 50 years. This family is a good example of a typical Hereditary Breast and Ovarian Cancer (HBOC) family. The risk for breast cancer in these families is increased because of the combination of both breast and ovarian cancers in the family, which highly points to BRCA1 mutations. The BRCA1 mutation probability as predicted by the BOADICEA model is high, 40.9%. The model then predicted her risk of breast cancer at only 13%. For a clinician, this risk estimation is hard to understand and feels illogical. It seems that in the risk prediction by Antoniou et al (2004) the presence of ovarian cancer is not important for the estimation of the breast cancer risk for this woman. The authors did not discuss this point. Recently, Jonker et al (2003) have published a genetic model to predict someone's breast cancer risk based on the family history of breast and ovarian cancer. This model can be considered as an extension of the Claus model combined with the BRCAPRO model (Claus et al, 1991; Parmigiani et al, 1998). In the Jonker et al model, the familial clustering of breast and ovarian cancer is explained by three genes, BRCA1, BRCA2 and a hypothetical third gene BRCAu. This third gene was modelled to explain all familial clustering of breast cancer unaccounted for by the BRCA1 and BRCA2 genes. The model parameters were estimated using published estimates of population incidence and relative risks. As well as the BOADICEA model, the Jonker et al model is not easy to use in clinical practice. For this reason, we extended the easy-to-use Claus tables into the ‘Claus plus method' based on the Jonker model (Claus et al, 1994; Van Asperen et al, 2004). Our method uses the Claus tables, but also incorporates information on the presence of ovarian cancer, bilateral breast cancer and whether there are more than two affected relatives. The formula we obtained simplifies risk estimation in familial breast cancer: The formula starts with an intercept of 0.08. This is the population risk for breast cancer and the basis for further risk estimation. The value of the Claus table should be multiplied by 0.4. The formula subsequently includes the information on ovarian cancer, bilateral breast cancer and more than two affected relatives. These characteristics in the formula are one or zero. This new method might offer a good alternative for breast cancer risk estimation in clinical practice. The ‘Claus plus method' is an easy applicable method for hand-written pedigrees and at the moment it is widely used in the Dutch cancer clinics. Based on the ‘Claus plus method', the predicted risk of breast cancer of the 40-year-old woman in Figure 3 in the Antoniou paper was 31%. Although we are still working on the validation of our method, this risk figure is more in agreement with the risks as observed in typical HBOC families. The authors have mentioned several improvements to be made for their multi-purpose BOADICEA model like genotype-specific incidence rates, risk for other cancers and allele frequencies. Besides this, we would like to recommend paying attention to the applicability for clinical practice. To attain full development for the BOADICEA model, the authors should be in close contact with the ultimate users in clinical practice.

Magnesium VitB6 Intake Reduces Central Nervous System Hyperexcitability in Children

Objective: Ionic magnesium (Mg2+) depletion has long been known to cause hyperexcitability with convulsive seizures in rodents, effects that have been reversed by treatment with magnesium (Mg). Metabolic disorders and genetic alterations are suspected in this pathology, in which Mg2+ transport and intracellular distribution may be reduced without change in serum Mg2+ concentrations. We evaluated the effects of Mg2+/vitamin B6 regimen on the behavior of 52 hyperexcitable children (under 15 years of age) and their families.Methods: To assess intracellular Mg2+, we measured intra-erthrocyte Mg2+ levels (ERC-Mg). Our reference values for normal subjects were 2.46 to 2.72 mmol/L. In 30 of the 52 hyperactive children, there were low ERC-Mg values: 2.041 ± 0.279 mmol/L). Combined Mg2+/vitamin B6 intake (100 mg/day) for 3 to 24 weeks restored normal ERC-Mg values (2.329 ± 0.386 mmol/L).Results: In all patients, symptoms of hyperexcitability (physical aggressivity, instability, scholar attention, hypertony, spasm, myoclony) were reduced after 1 to 6 months treatment. Other family members shared similar symptoms, had low ERC-Mg values, and also responded clinically to increased Mg2+/vitamin B6 intakes. Two typical families are described.Conclusion: This open study indicates that hyperexcitable children have low ERC-Mg with normal serum Mg2+ values, and that Mg2+/vitamin B6 supplementation can restore normal ERC-Mg levels and improve their abnormal behavior.

Rigidity for Families of Polarized Calabi–Yau Varieties

In this paper, we study the analogue of the Shafarevich conjecture for polarized Calabi–;Yau varieties. We use variations of Hodge structures and Higgs bundles to establish a criterion for the rigidity of families. We then apply the criterion to obtain that some important and typical families of Calabi–Yau varieties are rigid, for examples., Lefschetz pencils of Calabi–Yau varieties, strongly degenerated families (not only for families of Calabi–Yau varieties), families of Calabi–Yau varieties admitting a degeneration with maximal unipotent monodromy.

Family Income and Income Taxes during the Economic Recovery

Income tax relief passed since 2001 has lifted after-tax incomes for families in each of the last three years. With the application of the new 10 percent tax bracket, marriage penalty relief and child tax credit, the after-tax income of typical married-couple families with two children increased $1,233, or 2.2 percent, in real terms between 2000 and 2003. Compared to what after-tax income would have been without the tax reductions, tax savings in these three years bolstered after-tax income by a combined total of more than $3,500. This after-tax income measure reached a record high in 2003, and in 2001 through 2003 exceeded income levels of all years during the economic boom that ended in 2000. These data clearly show that middle-income families received significant relief from the 2001 and 2003 tax acts.

Multiple colonization of the deep sea by the Asellota (Crustacea: Peracarida: Isopoda)

Despite its extreme environmental conditions the deep sea harbors a unique and species-rich fauna of mostly unknown age and phylogeny. Asellote isopods have undergone their most impressive radiation in the deep sea, being found at all depths down to the deepest trench. Here we present the first molecular evidence for the phylogenetic origin of this remarkable array of deep-sea crustaceans, based on 30 new DNA-sequences of the complete 18s rRNA gene of specimens collected at depths down to 4543 m in the South Atlantic and South Polar Ocean. The results show that most of these isopod lineages belong to a single ancient clade. They evolved in situ in large oceanic depths and survived several climatic changes, but the lack of fossils and of a suitable molecular clock model prevents a precise dating of this radiation. The monophyly of typical deep-sea families, for example the Haploniscidae, Ischnomesidae or Munnopsidae, is well supported by different methods of analysis, while the monophyly of the Janiridae is rejected.

Complete loss of the cytoplasmic carboxyl terminus of the KCNQ2 potassium channel: a novel mutation in a large Czech pedigree with benign neonatal convulsions or other epileptic phenotypes.

Benign neonatal familial convulsions (BNFCs) represent a rare epileptic disorder with autosomal dominant mode of inheritance. To date, two voltage-gated potassium (K+) channel genes, KCNQ2 and KCNQ3, have been identified in typical BNFC families. The study of new pedigrees may help detect new mutations and define genotype-phenotype correlations. A large Czech family was detected in which BNFC was inherited together with a broad range of various nonneonatal epileptic phenotypes. Genetic linkage study and direct mutation analysis were performed to find the disease-causing mutation. In seven patients with BNFCs and no recurrence of seizures, a novel two-base-pair deletion (1369del2) was identified within the coding sequence of the KCNQ2 gene. The mutation led to a putative protein that lacked nearly all its carboxyl terminus part, which plays a critical role for the accurate expression of the functional K+ channels. Three patients with generalized tonic-clonic seizures (GTCSs), all without any history of BNFCs, also displayed 1369del2. Three other patients with other idiopathic epileptic phenotypes did not have the mutation. A novel 2-bp deletion within the coding sequence of the potassium channel KCNQ2 gene was detected in patients from a large and heterogeneous family with BNFCs or non-BNFC seizures.

Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders.

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by the combined occurrence of tumours of the parathyroid glands, pancreatic islet cells and anterior pituitary gland. Mutation analysis of the MEN1 gene has enabled the genetic diagnosis of patients with MEN1. Two MEN1-related disorders - familial isolated hyperparathyroidism (FIHP) and familial pituitary adenoma - are considered to be variants of MEN1, or at least to be incompletely expressed variants. Germline mutations of the MEN1 gene have been reported in some with FIHP, but familial pituitary adenoma usually lacks the MEN1 mutation and has been described as a genetically distinct disorder. In this work, we investigated five Korean families with MEN1, one family with FIHP and one family with familial pituitary adenoma. Polymerase chain reaction (PCR)-based single-strand conformation polymorphism (PCR-SSCP) analysis, denaturing high-performance liquid chromatography (DHPLC) and sequencing were used to detect the MEN1 mutations. Screening of the genetic variations of the MEN1 gene revealed four germline mutations in five typical MEN1 families. All four germline mutations led to truncated proteins or a change in the amino acids of the functional domains. In this study, we identified three novel MEN1 germline mutations (969C >A, 973G >C and 1213C >T) and one previously reported mutation (200-201insAGCCC). The frequency of the MEN1 germline mutation in Korean MEN1 families (four of five; 80%) was similar to those reported previously. In accordance with previous studies, no MEN1 germline mutation was detected in two families with FIHP or familial pituitary adenoma.

Association of MICA-A5.1 allele with susceptibility to celiac disease in a family study

Objective The aim of this study was to analyze the role of the major histocompatibility complex class I chain-related gene A (MICA) transmembrane polymorphism in celiac disease (CD) susceptibility. Methods Sixty-one celiac Spanish families were genotyped for MICA transmembrane polymorphism by a polymerase chain reaction method combined with fluorescent technology. A transmission disequilibrium test was performed to investigate the preferential transmission of MICA alleles to the affected offspring. Results The MICA A5.1 allele was shown to be significantly transmitted to the affected siblings. This association was independent of the CD-predisposing DQ2 haplotype. Additionally, we classified our celiac families into typical and atypical groups as we found a significant association with MICA A5.1 in typical celiac families. There was also an association tendency with atypical families. Conclusions Our data suggest that the MICA A5.1 allele is associated with CD development independently of DQ2-extended haplotype and clinical forms of CD.

Association of MICA-A5.1 allele with susceptibility to celiac disease in a family study.

The aim of this study was to analyze the role of the major histocompatibility complex class I chain-related gene A (MICA) transmembrane polymorphism in celiac disease (CD) susceptibility. Sixty-one celiac Spanish families were genotyped for MICA transmembrane polymorphism by a polymerase chain reaction method combined with fluorescent technology. A transmission disequilibrium test was performed to investigate the preferential transmission of MICA alleles to the affected offspring. The MICA A5.1 allele was shown to be significantly transmitted to the affected siblings. This association was independent of the CD-predisposing DQ2 haplotype. Additionally, we classified our celiac families into typical and atypical groups as we found a significant association with MICA A5.1 in typical celiac families. There was also an association tendency with atypical families. Our data suggest that the MICA A5.1 allele is associated with CD development independently of DQ2-extended haplotype and clinical forms of CD.

Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer

Hereditary nonpolyposis colon cancer (HNPCC) is associated with malfunction of postreplicative mismatch repair (MMR). While a majority of HNPCC-associated mutations in the MMR genes MLH1, MSH2, or MSH6 genes cause truncations—and thus loss of function—of the respective polypeptides, little is currently known about the biochemical defects associated with nontruncating mutations. We studied the interactions of six MLH1 variants, carrying either missense mutations or in-frame deletions, with normal PMS2 and tested the functionality of these heterodimers of MLH1 and PMS2 (MutLα) in an in vitro MMR assay. Three MLH1 carboxy-terminal mutations, consisting of internal deletions of exon 16 (amino acids 578–632) or exon 17 (amino acids 633–663), or a missense R659P mutation in exon 17, affected the formation of a functional MutLα. Interestingly, mutations C77R and I107R in the amino-terminal part of MLH1 did not affect its heterodimerization with PMS2. The complexes MLH1(C77R)/PMS2 and MLH1(I107R)/PMS2, however, failed to complement a MMR-deficient extract lacking a functional MutLα. As all these five mutations were identified in typical HNPCC families and produce nonfunctional proteins, they can be considered disease-causing. In contrast, the third amino-terminal mutation S93G did not affect the heterodimerization, and the MLH1(S93G)/PMS2 variant was functional in the in vitro MMR assay, given thus the nature of the HNPCC family in question. Although the missense mutation segregates with the disease, the mean age of onset in the family is unusually high (∼65 years). © 2002 Wiley-Liss, Inc.

Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer

Hereditary nonpolyposis colon cancer (HNPCC) is associated with malfunction of postreplicative mismatch repair (MMR). While a majority of HNPCC-associated mutations in the MMR genes MLH1, MSH2, or MSH6 genes cause truncations-and thus loss of function--of the respective polypeptides, little is currently known about the biochemical defects associated with nontruncating mutations. We studied the interactions of six MLH1 variants, carrying either missense mutations or in-frame deletions, with normal PMS2 and tested the functionality of these heterodimers of MLH1 and PMS2 (MutL(alpha)) in an in vitro MMR assay. Three MLH1 carboxy-terminal mutations, consisting of internal deletions of exon 16 (amino acids 578-632) or exon 17 (amino acids 633-663), or a missense R659P mutation in exon 17, affected the formation of a functional MutL(alpha). Interestingly, mutations C77R and I107R in the amino-terminal part of MLH1 did not affect its heterodimerization with PMS2. The complexes MLH1(C77R)/PMS2 and MLH1(I107R)/PMS2, however, failed to complement a MMR-deficient extract lacking a functional MutL(alpha). As all these five mutations were identified in typical HNPCC families and produce nonfunctional proteins, they can be considered disease-causing. In contrast, the third amino-terminal mutation S93G did not affect the heterodimerization, and the MLH1(S93G)/PMS2 variant was functional in the in vitro MMR assay, given thus the nature of the HNPCC family in question. Although the missense mutation segregates with the disease, the mean age of onset in the family is unusually high (approximately 65 years).

Heritability of plasma amyloid beta in typical late-onset Alzheimer's disease pedigrees.

Plasma amyloid beta42 peptide (Abeta42) levels are significantly elevated in all genetic forms of early-onset Alzheimer's disease caused by familial Alzheimer's disease mutations or Down's syndrome. Moreover, recent studies have determined that both plasma Abeta42 and Abeta40 levels are significantly elevated in late-onset Alzheimer's disease (LOAD) patients, their cognitively normal first-degree relatives, and members of typical LOAD families when compared to appropriate controls. To determine the magnitude of the genetic component affecting plasma Abeta levels, we estimated the heritability of plasma Abeta42 and Abeta40 in 15 extended, multigenerational LOAD pedigrees, using a variance components method. Heritability estimates as high as 73 and 54% were found for plasma Abeta42 and Abeta40 levels, respectively. Inclusion of the ApoE epsilon4 dosage as a covariate was not found to have a significant effect on the heritability of these traits. These results suggest that genetic determinants other than ApoE account for a very substantial percentage of the phenotypic variance in plasma Abeta levels. The high heritability and the significant elevation of these traits in LOAD pedigrees suggest that at least some of the genetic determinants of plasma Abeta levels may lead to elevated Abeta and LOAD in these families. Thus, we suggest that plasma Abeta levels are quantitative traits that may be excellent surrogate markers for use in linkage analysis to identify loci that are important in typical LOAD.

Adult Children Helping Older Parents

Using the 1993 Panel Study of Income Dynamics, the authors examine help given to older parents in typical American families. Daughters and sons not in couples were more likely to help than those in couples, and gave substantially more hours. In couples, daughters were less likely to help than sons, but they helped for considerably more hours. Black daughters helped at least as commonly as White daughters, and did so for substantially more hours than either White daughters or sons of either race. Results suggest that Black sons may help less commonly than White sons. Black sons who help, however, do so for at least as many hours as White sons. Findings suggest that changes in the Black American family have not produced the notable intergenerational relations breakdown anticipated by some researchers. Results also illuminate the important role of sons in family help and suggest that changing marriage patterns may not reduce help to older parents.

Mapping of the second Friedreich's ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity.

Friedreich's ataxia (FRDA), the most-common form of autosomal recessive ataxia, is inherited in most cases by a large expansion of a GAA triplet repeat in the first intron of the frataxin (X25) gene. Genetic heterogeneity in FRDA has been previously reported in typical FRDA families that do not link to the FRDA locus on chromosome 9q13. We report localization of a second FRDA locus (FRDA2) to chromosome 9p23-9p11, and we provide evidence for further genetic heterogeneity of the disease, in a family with the classic FRDA phenotype.

Clinicopathological and molecular genetic analysis of 4 typical Chinese HNPCC families.

To study the clinicopathological and molecular genetic characteristics of typical Chinese hereditary nonpolyposis cotorectal cancer (HNPCC) families. Four typical Chinese HNPCC families were analyzed using microdissection, microsatellite instability analysis, immunostaining of hMSH2 and hMLH1 proteins and direct DNA sequencing of hMSH2 and hMLH1 genes. All five tumor tissues of 4 probands from the 4 typical Chinese HNPCC families showed microsatellite instability at more than two loci (MSI-H or RER+ phenotype). Three out of the 4 cases lost hMSH2 protein expression and the other case showed no hMLH1 protein expression. Three pathological germline mutations (2 in hMSH2 and 1 in hMLH1), which had not been reported previously, were identified. The same mutations were also found in other affected members of two HNPCC families,respectively. Typical Chinese HNPCC families showed relatively frequent germline mutation of mismatch repair genes. High-level microsatellite instability and loss of expression of mismatch repair genes correlated closely with germline mutation of mismatch repair genes. Microsatellite instability analysis and immunostaining of mismatch repair gene might serve as effective screening methods before direct DNA sequencing. It is necessary to establish clinical criteria and molecular diagnostic strategies more suitable for Chinese HNPCC families.

Arbuscular mycorrhizal colonization of halophytes in Central European salt marshes

Halophytes from both coastal and inland Central European salt marshes were examined for colonization by arbuscular mycorrhizal (AM) fungi. Plants from different families were strongly colonized but the degree of colonization varied with the individual plant and apparently during the vegetation period, too. Members of the typical non-mycorrhizal families like Armeria maritima of the Plumbaginaceae and Salicornia europaea of the Chenopodiaceae were found to be colonized, particularly in the drier salt marshes. High numbers of Glomus spores were found in the saline soils, especially those of the inland locations examined. Approximately 80% of these spores were from Glomus geosporum as shown by a typical restriction fragment length polymorphism (RFLP) pattern of the amplified internal transcribed spacer regions. The present study demonstrates that RFLP analysis is useful when screening habitats for the occurrence of mycorrhizal fungi which can be identified only with difficulty by morphological criteria.

Inheritance of a Stable Mutation in a Family with Early-Onset Disease

Autosomal/dominant polycystic kidney disease (ADPKD) exhibits a high inter- and intrafamilial heterogeneity partly explained by the involvement of at least 3 different genes in the disorder transmission. PKD1, the major locus, is located on chromosome 16p. The occurrence of very early-onset cases of ADPKD (sometimes in utero) in a few PKD1 families or the increased severity of the disease in successive generations raise the question of anticipation. This is a subject of controversial discussion. This report deals with the molecular analysis in families with very early-onset ADPKD. The finding of the same stable mutation with such different phenotypes rules out a dynamic mutation. The molecular basis of severe childhood PKD in typical ADPKD families remains unclear; it may include segregation of modifying genes or unidentified factors and the two-hit mechanism.

Lack of Association of the Norrie Disease Gene with Retinoschisis Phenotype

Purpose: It has been reported recently that mice carrying a disrupted Norrie disease gene produced alterations in the murine eye that are similar to congenital retinoschisis. Therefore, it was of interest to determine whether mutations in the Norrie disease gene can account for the disease in families with retinoschisis that do not carry mutations in the retinoschisis gene. Methods: The patient set comprised 5 cases of retinoschisis (1 familial and 4 sporadic), all unrelated to each other. Fundus examination of affected individuals showed foveal and peripheral schisis, and the visual acuity range was 20/40–20/60. Peripheral blood specimens were collected from affected and unaffected family members. DNA was extracted and amplified by polymerase chain reaction amplification of exons of the Norrie disease gene. The amplified products were sequenced by the dideoxy chain termination method. Results: The data revealed no disease-specific sequence alterations in the Norrie disease gene. Conclusion: Although we cannot completely exclude the possibility of the Norrie disease gene as a candidate gene, the above results suggest that the structural and functional changes in the Norrie disease gene are not associated with clinically typical retinoschisis families that do not contain mutations in the coding regions and splice sites of the retinoschisis gene.

Expression of the barley dehydrin multigene family and the development of freezing tolerance.

Dehydrins (DHNs; LEA D11) are one of the typical families of plant proteins that accumulate in response to dehydration, low temperature, osmotic stress or treatment with abscisic acid (ABA), or during seed maturation. We previously found that three genes encoding low-molecular-weight DHNs (Dhn1, Dhn2 and Dhn9) map within a 15-cM region of barley chromosome 5H that overlaps a QTL for winterhardiness, while other Dhn genes encoding low- and high-molecular-weight DHNs are located on chromosomes 3H, 4H and 6H. Here we examine the expression of specific Dhn genes under conditions associated with expression of the winterhardiness phenotype. Plants grown at 4 degrees C or in the field in Riverside, California developed similar, modest levels of freezing tolerance, coinciding with little low-MW Dhn gene activity. Dicktoo (the more tolerant cultivar) and Morex (the less tolerant) grown in Saskatoon, Canada expressed higher levels of expression of genes for low-MW DHNs than did the same cultivars in Riverside, with expression being higher in Dicktoo than Morex. Dehydration or freeze-thaw also evoked expression of genes for low MW DHNs, suggesting that the dehydration component of freeze-thaw in the field induces low expression of genes encoding low-MW DHNs. These observations are consistent with the hypothesis that the major chilling-induced DHNs help to prime plant cells for acclimation to more intense cold, which then involves adaptation to dehydration during freeze-thaw cycling. A role for chromosome 5H-encoded DHNs in acclimation to more intense cold seems possible, even though it is not the basis of the major heritable variation in winterhardiness within the Dicktoo x Morex population.

Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk

We report the functional expression of four KCNQ1 mutations affecting arginine residues and resulting in Romano-Ward (RW) and the Jervell and Lange-Nielsen (JLN) congenital long QT syndromes. The R539W and R190Q mutations were found in typical RW families with an autosomal dominant transmission. The R243H mutation was found in a compound heterozygous JLN patient who presents with deafness and cardiac symptoms. The fourth mutation, R533W, was a new case of recessive form of the RW syndrome since homozygous carriers experienced syncopes but showed no deafness, whereas the heterozygous carriers were asymptomatic. The R190Q mutation failed to produce functional homomeric channels. The R243H, R533W and R539W mutations induced a positive voltage shift of the channel activation but only when co-expressed with IsK, pointing out the critical role of these positively charged residues in the modulation of the gating properties of KvLQT1 by IsK. The positive shift induced by R533W was merely 15%. This small effect was compatible with the recessive character of the RW phenotype transmission. The average QTc was significantly longer (P < 0.01) in patients carrying mutations inducing a total loss of channel function and those patients were also prone to cardiac adverse symptoms (whether syncopes or sudden death) to a greater extent (62 vs. 21%, P < 0.001). Novel mutations are described that induce a voltage shift of the channel activation only in the presence of IsK. They appear associated with a milder cardiac phenotype.