A compound-heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype.

We describe here the identification of defined mutations in both alleles of the fibrillin gene (FBN1) in a compound-heterozygote Marfan syndrome (MFS) child who had a very severe form of MFS resulting in death from cardiac failure at the age of 4 mo. The nonconsanguineous parents were both affected with MFS. The father's heterozygous point mutation has earlier been reported to result in W217G substitution, the mother was here shown to carry a heterozygous point mutation resulting in G2627R substitution, and the child had inherited both these mutations. The mutant FBN1 alleles were demonstrated to be transcribed with equal efficiency compared with the normal alleles, but metabolic labeling of fibroblast cultures from the child and both parents showed reduced biosynthesis and secretion of profibrillin. Also, the respective amounts of fibrillin in cell-culture media and extracellular-matrix extracts were markedly diminished, particularly in the cell cultures from father and child. In addition, immunofluorescence analysis of the cell cultures of all three family members revealed a drastically reduced amount of microfibrils, and virtually no visible fibrils could be seen in the case of the compound-heterozygote child. These findings demonstrate incomplete dominance of fibrillin mutations and underline the fatal consequences of the complete absence of normal fibrillin molecules in the microfibrils.     

Molecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions.

A male child with multiple congenital anomalies initially was clinically diagnosed as having Smith-Lemli-Opitz syndrome (SLOS). Subsequent cytogenetic studies revealed an interstitial deletion of 17p11.2, which is associated with Smith-Magenis syndrome (SMS). Biochemical studies were not supportive of a diagnosis of SLOS, and the child did not display the typical SMS phenotype. The father's karyotype showed a paracentric inversion of 17p, with breakpoints in p11.2 and p13.3, and the same inversion was also found in two of the father's sisters. FISH analyses of the deleted and inverted 17p chromosomes indicated that the deletion was similar to that typically seen in SMS patients and was found to bracket the proximal inversion breakpoint. Available family members were genotyped at 33 polymorphic DNA loci in 17p. These studies determined that the deletion was of paternal origin and that the inversion was of grandpaternal origin. Haplotype analysis demonstrated that the 17p11.2 deletion arose following a recombination event involving the father's normal and inverted chromosome 17 homologues. A mechanism is proposed to explain the simultaneous deletion and apparent "reinversion" of the recombinant paternal chromosome. These findings have implications for prenatal counseling of carriers of paracentric inversions, who typically are considered to bear minimal reproductive risk.     

Characterization of a spontaneous mutation to a beta-thalassemia allele.

We have studied a nuclear family containing a single child with severe beta-thalassemia intermedia, a Greek-Cypriot mother with hematological findings of beta-thalassemia trait, and a Polish father who is hematologically normal. Since both the child and her father were heterozygous for a DNA polymorphism within the beta-globin gene, it was possible to clone and sequence the beta-globin gene identical by descent from both the child and her father. A nonsense mutation in codon 121 (GAA----TAA) was found in the beta-globin gene of the child, while the same gene from her father lacked this mutation and was normal. This mutation has not been previously observed among over 200 beta-thalassemia genes characterized in Caucasians. Since the mutation eliminates an EcoRI site in the beta-globin gene, we could show that the mutation is not present in genomic DNA of the father. To rule out germinal mosaicism, sperm DNA of the father was also digested with EcoRI, and the mutant EcoRI fragment was not observed under conditions that would detect the mutation if it were present in at least 2% of sperm cells. Routine HLA and blood group testing supported stated paternity. In addition, studies with 17 DNA probes that detect multiple allele polymorphisms increased the probability of stated paternity to at least 10(8):1. These data provide evidence that the G----T change in codon 121 of the beta-globin gene in the child is the result of a spontaneous mutation that occurred during spermatogenesis in a paternal germ cell.     

Parents' testosterone and children's perception of parent-child relationship quality

We examine the link between parental testosterone and children's perceptions of their relationship with their mother and father. Using data from 352 predominantly white working and middle class families, we find no direct link between mother's and father's testosterone and parent–child closeness. However, the association between mothers' testosterone and mother–child closeness appears to be influenced by the quality of two other family relationships. When father's marital satisfaction is low, mothers with high testosterone have a poorer relationship with their children. And, when fathers report low levels of intimacy with their children, high testosterone women have a poorer relationship with their children. No comparable associations were observed among fathers.     

Paternal investment and status-related child outcomes: timing of father's death affects offspring success

Recent work in human behavioural ecology has suggested that analyses focusing on early childhood may underestimate the importance of paternal investment to child outcomes since such investment may not become crucial until adolescence or beyond. This may be especially important in societies with a heritable component to status, as later investment by fathers may be more strongly related to a child's adult status than early forms of parental investment that affect child survival and child health. In such circumstances, the death or absence of a father may have profoundly negative effects on the adult outcomes of his children that cannot be easily compensated for by the investment of mothers or other relatives. This proposition is tested using a multigenerational dataset from Bangalore, India, containing information on paternal mortality as well as several child outcomes dependent on parental investment during adolescence and young adulthood. The paper examines the effects of paternal death, and the timing of paternal death, on a child's education, adult income, age at marriage and the amount spent on his or her marriage, along with similar characteristics of spouses. Results indicate that a father's death has a negative impact on child outcomes, and that, in contrast to some findings in the literature on father absence, the effects of paternal death are strongest for children who lose their father in late childhood or adolescence.     

Analysis of the red cell membrane in a family with hereditary elliptocytosis — total or partial of protein 4.1

Summary In a 12-year-old boy carrying a clinically silent elliptocytosis, we observed a total lack of red cell membrane band 4.1. Band 4.1 was partially absent in the father who also displayed a clinically silent elliptocytosis and, remarkably, in the mother although she presented normal discocytes. Band (2 and 2.1) phosphorylation was sharply reduced in the three persons examined. In the propositus and his mother, but not in his father, a clearly phosphorylated band appeared at the level of band 4.2. We suggest that the father and the mother carry two distinct alleles affecting differently the interactions, within the spectrin-actin protein 4.1 complex. The father's allele is elliptocytogenic in the heterozygous state and, among other molecular alterations, prevents the attachment of protein 4.1. The mother's allele is morphologically silent in the heterozygous state, yet it also affects the binding of protein 4.1, possibly because the latter is shortened. The propositus, being doubly heterozygous, has the same morphological phenotype as his father, but his protein 4.1 electrophoretic phenotype is the addition of both parental phenotypes. The distinct phosphorylation patterns in the region of bands 4.1 and 4.2 are also consistent with the two-allele hypothesis.     

Salivary hormone concentrations in mothers and fathers becoming parents are not correlated

A time- and date-matched set of saliva samples (N = 229) from nine couples first expecting, and then caring for, their first child were used to test whether hormone changes in the father could be predicted by the hormonal status of the mother. Testosterone, cortisol, and estradiol were quantified from saliva. Neither testosterone nor estradiol concentration was correlated within couples before or after the birth, although there was a positive correlation for cortisol concentration in the mother and father before the birth. As the hormone that might be influenced by chemical signals, that already played a similar role in men and women, and that had been empirically linked to paternal behavior, cortisol concentration was also compared with sex steroid concentrations. The mother's cortisol concentration was positively correlated to the father's testosterone concentration, and the mother's testosterone concentration was positively correlated with the father's cortisol concentration. However, both effects were similar in magnitude to the cortisol to cortisol correlation, and all could parsimoniously be explained by similar responses to a shared environment. Thus, this analysis rejects parallels in peripheral hormone concentrations of estradiol, testosterone, and cortisol in mothers and fathers. However, the available data were not able to test or reject hypotheses about local neuroendocrine homology, nor to control for masking effects of other hormonal demands on men and women, nor to determine the relative importance of shared environment versus mother-father signaling.     

Tracking of familial resemblance for resting blood pressure over time in the Québec Family Study

The etiology of familial resemblance for systolic (SBP) and diastolic (DBP) blood pressure, both within a single time point as well as across time points, was assessed to determine how familial etiologies underlying a trait may change across time. SBP and DBP measurements were taken roughly 12 years apart in family members participating in the longitudinal Québec Family Study. A longitudinal (bivariate) familial correlation model yields 3 types of correlations: intraindividual cross-time (e.g., father's BP at time 1 with his own BP at time 2); interindividual within-time (e.g., father time 1 with child time 1); and interindividual cross-time (e.g., father time 1 with child time 2). In addition, the change in BP across time (i.e., time 1-time 2) is examined using a univariate family correlation model. This combined method is useful in assessing the degree to which the same familial factors are operating across time (interindividual cross-time correlations), as well as the degree to which different heritable components are involved across time (change score). Maximal heritabilities for SBP were about 70% at each time point, while for DBP the heritability was larger at time 1 (87%) than time 2 (39%). Both the change scores (48% for SBP and 54% for DBP) and the cross-time comparisons (58% to 72% for SBP and 63% to 65% for DBP) evidenced significant familial resemblance. These results illustrate how simple methodologies can be used to specify how familial etiologies underlying a trait may change across time. For BP, the model includes unique familial factors that are specific to each time measurement, and an additional familial factor which is common to both time points. The factors leading to differences in longitudinal familial resemblance for BP (i.e., the unique factors) may be primarily genetic in origin, while those leading to stability across time may include both genetic and familial environmental effects. Sex and/or age interactions with the genotypes are also suggested.     

Complete deficiency of constitutive heterochromatin on a human chromosome 9

Summary In cultured amniotic fluid cells a mediocentric chromosome 9 appeared to be completely deficient in constitutive heterochromatin when stained with distamycin A and DAPI. In addition, this deficient chromosome was found in a blood cell culture from the father. Both the father and the child after birth were phenotypically normal. Evidently, a considerable heterozygotic deficit of chromosome 9 heterochromatin can be tolerated without affecting the phenotype. The heterochromatin defect was also shown by G11-staining. Distamycin A-DAPI staining is highly reproducible and is recommended as a fluorescent alternative to often less successful G11-methods for the detection of heteromorphism of chromosome 9.     

Immunologic studies with LFA-1- and Mo1-deficient lymphocytes from a patient with recurrent bacterial infections

A patient and his parents, deficient for lymphocyte function associated antigen-1 (LFA-1) and Mo1 (OKM1), were studied with respect to leukocyte surface marker expression and functional properties. The patient had a history of severe recurrent bacterial infections. Two siblings had already died of bacterial infections. The patient's granulocytes, monocytes, and lymphocytes expressed low but detectable amounts (less than or equal to 10%) of LFA-1 and Mo1. Intracellularly, LFA-1 and Mo1 (OKM1) were detectable and LFA-1 expression was enhanced on patient T cells stimulated with phytohemagglutinin. Granulocytes and monocytes of both the patient's parents expressed markedly decreased amounts of LFA-1 and Mo1. Lymphocytes of the mother expressed 40 to 60% of the amount of LFA-1 expressed on control lymphocytes, but his father's lymphocytes showed a normal LFA-1 expression. Granulocytes of the patient and of his deceased sister showed normal phagocytosis, but they had a dysfunction in the activation of the oxidative metabolism. Functional activities mediated by patient T cells were all normal. Moreover, all lymphocyte functions, including killer (K), natural killer (NK), cytotoxic T cell activity, helper activity for in vitro immunoglobulin (Ig) production by normal B cells, and PHA-induced proliferation were inhibitable by anti-LFA-1 monoclonal antibodies. K and NK activity mediated by patient leukocytes was 100-fold more sensitive to the inhibiting effect of anti-LFA-1 antibody than K and NK activity of normal donor leukocytes. Thus, although the amount of LFA-1 expressed was strongly reduced, it was still sufficient and required for the functional activity exhibited by patient T cells. The major functional defect observed with leukocytes of the patient and his father was an apparent B cell defect. B cells of the father and of the patient failed to produce Ig in the pokeweed mitogen (PWM)-driven system. The B cells of patient and of his father only produced Ig when cultured with T cells of the father, and not with normal donor T cells or T cells of the mother, in the presence of exogenous interleukin 2 (IL 2). In addition, the father's B cells produced Ig when cocultivated with patient T cells in the IL 2-driven system. This restriction of helper T cell activity is noteworthy because PWM- and IL 2-driven Ig synthesis by normal lymphocytes show no histocompatibility requirements between cooperating T and non-T cell populations.(ABSTRACT TRUNCATED AT 400 WORDS)     

Glucose phosphate isomerase deficiency with hereditary hemolytic anemia in a Spanish family: clinical and familial studies.

A new case of glucose phosphate isomerase deficiency associated with cogenital nonspherocytic hemolytic anemia is described in a 12-year-old girl of Spanish origin. The parents exhibited erythrocyte glucose phosphate isomerase activity between 50 and 60% of normal. The enzyme of the propositus had normal Michaelis-Menten constants both for F-6-P and G-6-P, but abnormal pH optimum and decreased heat stability at 48 degrees C. On starch-gel electrophoresis the father's enzyme was normal but the mother's showed a cathodic migrating band in addition to the normal one. The enzyme from the propositus exhibited only one band with cathodal mobility of 116% of the main band found in normal subjects. It is postulated that the propositus is double heterozygous for two abnormal alleles, and the mother contributes a mutant allele with abnormal electrophoretic mobility and thermolability at 48 degrees C whereas the father contributes an allele without enzymatic activity.     

Prolactin, Oxytocin, and the development of paternal behavior across the first six months of fatherhood

Animal studies have implicated the neuropeptides Prolactin (PRL) and Oxytocin (OT) in processes of maternal bonding and PRL has similarly been shown to play a role in the neurophysiology of fatherhood. Yet, very little is known on the involvement of PRL and OT in human fathering. Forty-three fathers and their firstborn infant were seen twice: in the second and sixth postpartum months. Paternal plasma PRL and OT were sampled at both time-points and analyzed with ELISA methods. At six months fathers were videotaped interacting with their child in social and exploratory play contexts and interactions were micro-analyzed for father-infant Affect Synchrony and father facilitation of child toy exploration. PRL and OT showed high individual stability across time and were correlated at the second observation. PRL was related to father-infant Coordinated Exploratory Play in the toy context whereas OT was associated with father-infant Affect Synchrony in the social context. Results point to the role of PRL and OT in the development of human fathering and underscore their differential relations with patterns of paternal care.     

Parental somatic and germ-line mosaicism for a multiexon deletion with unusual endpoints in a type III collagen (COL3A1) allele produces Ehlers-Danlos syndrome type IV in the heterozygous offspring.

Ehlers-Danlos syndrome (EDS) type IV is a dominantly inherited disorder that results from mutations in the type III collagen gene (COL3A1). We studied the structure of the COL3A1 gene of an individual with EDS type IV and that of her phenotypically normal parents. The proband was heterozygous for a 2-kb deletion in COL3A1, while her father was mosaic for the same deletion in somatic and germ cells. In fibroblasts from the father, approximately two-fifths of the COL3A1 alleles carried the deletion, but only 10% of the COL3A1 alleles in white blood cells were of the mutant species. The deletion in the mutant allele extended from intron 7 into intron 11. There was a 12-bp direct repeat in intron 7 and intron 11, the latter about 60 bp 5' to the junction. At the breakpoint there was a duplication of 10 bp from intron 11 separated by an insertion of 4 bp contained within the duplicated sequence. The father was mosaic for the deletion so that the gene rearrangement occurred during his early embryonic development prior to lineage allocation. These findings suggest that at least some of the deletions seen in human genes may occur during replication, rather than as a consequence of meiotic crossing-over, and that they thus have a risk for recurrence when observed de novo.     

False paternity exclusion in the Rh system: use of cytofluorometry analysis

In a two-men paternity testing analysis, the first putative father was definitely excluded by six blood group systems; the second one was apparently excluded in the Rh system. In fact, an analysis by flow-cytometry demonstrated that this false exclusion was due to the presence of a D--haplotype in the father and child.     

Occult HBV Infection May Be Transmitted through Close Contact and Manifest as an Overt Infection

The importance of transmission of occult HBV infection (OBI) via transfusion, organ transplantation and hemodialysis has been widely recognized. However, data regarding the transmission of OBI through close contact remain limited. In this study, serum samples were obtained from a child and his parents. The child had received the standard vaccination regimen at birth and produced protective antibody. Sera were tested for HBV serological markers. Nested PCR assays were used to detect HBV DNA and the amplicons were cloned and their sequences subjected to phylogenetic analysis. The results showed that both parents had occult infections while the child had an overt infection. Twelve, eleven and nine clones, from the father, mother and son, respectively, were sequenced. Serotypes adrq+, ayw1, ayw and ayr were found in the father and ayw1, adw2 and adwq+ in the mother; adrq+ was the only serotype in son. Genotype B, subgenotype C2 and a recombinant were identified in the father and genotype B, subgenotype C5 and three recombinants were found in the mother. Subgenotype C2 was the only genotype identified in the child. A phylogenetic tree showed that all of the child’s sequences and most of the father’s sequences clustered together. However, none of mother’s sequences clustered with those of the child. The surface gene from the child and his father had the same amino acid substitution pattern (T118K, T123N and G145A). We concluded that the father was the source of the son’s HBV infection, suggesting that occult HBV infection may be transmitted through close contact and manifest as an overt infection.     

A Gc silent allele encountered in a paternity case

A father-child incompatibility only in the Gc system was detected in a paternity case tested at our laboratory. Quantitative determination revealed that the Gc level in the two individuals was less than 50% of the normal mean value. Evaluation of the probability calculation for the putative father using all other markers showed that he was the biological father with a very high probability. Thus it was concluded that a silent allele Gc*QO was transmitted from the father to the child.     

Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers.

Two novel mutations in the sex-determining gene SRY were identified by screening DNA from 30 sex-reversed XY females by using the SSCP assay. Both point mutations lead to an amino acid substitution in the DNA-binding high-mobility-group domain of the SRY protein. The first mutation, changing a serine at position 91 to glycine, was found in a sporadic case. The second mutation, leading to replacement of a highly conserved proline at position 125 with leucine, is shared by three members of the same family, two sisters and a half sister having the same father. The mutant SRY proteins showed reduced DNA-binding ability in a gel-shift assay. Analysis of lymphocyte DNA from the respective fathers revealed that they carry both the wild-type and the mutant version of the SRY gene. The fact that both fathers transmitted the mutant SRY copy to their offspring implies that they are mosaic for the SRY gene in testis as well as in blood, as a result of a mutation during early embryonic development.     

A silent transferrin allele in a Finnish family

In a Finnish family a silent allele was found in the transferrin (Tf) system. As determined by gel electrophoresis and immunoblotting, the Tf type of the father was CD, the mother C, and the child D. The serum Tf concentration in grandmother, mother, and child was less than 50% of normal.     

Inter-generation social mobility modifies framingham risk score in Polish middle-aged men, but not in women

In modern societies, there are regular social gradients in most health parameters, and also in the structure of morbidity and mortality. However, the significance of inter-generation social mobility for general health status still remains equivocal. This study was therefore performed in order to compare the effect of social mobility on coronary heart disease (CHD) risk between middle-aged Polish men and women. A total of 342 men and 458 women, aged 40 and 50 and inhabitants of Wroc?aw, were examined. Risk of CHD was estimated using the Framingham Risk Score (FRS), calculated for each individual. Social mobility was defined as an inter-generation change in social status expressed as educational level between the examined individual and his/her father. Using two-variable regression models, it was demonstrated that FRS in men was determined by both their father's education level (beta=0.33, p<0.0001) and inter-generation change in educational status (beta=0.18, p=0.008). In contrast, FRS in women was related only to their father's education level (beta=0.35, p<0.0001), but not to inter-generation social mobility (beta=0.35, p=0.25). In particular, an incremental change in educational level among those men whose father had finished primary school at the very most or among those whose father had finished basic trade school was accompanied by a significant decrease in FRS (F=4.12, p=0.009 and F=3.25, p=0.04, respectively). It is concluded that inter-generation social mobility modifies CHD risk (as estimated using FRS) in middle-aged Polish men, but not in women. The precise mechanisms responsible for the observed sex difference in this phenomenon need to be established in further studies.