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PubMed2000

Genetic determinants of acute hypoxic ventilation: patterns of inheritance in mice.

Acutely lowering ambient O(2) tension increases ventilation in many mammalian species, including humans and mice. Inheritance patterns among kinships and between mouse strains suggest that a robust genetic influence determines individual hypoxic ventilatory responses (HVR). Here, we tested specific genetic hypotheses to describe the inheritance patterns of HVR phenotypes among two inbred mouse strains and their segregant and nonsegregant progeny. Using whole body plethysmography, we assessed the magnitude and pattern of ventilation in C3H/HeJ (C3) and C57BL/6J (B6) progenitor strains at baseline and during acute (3-5 min) hypoxic [mild hypercapnic hypoxia, inspired O(2) fraction (FI(O(2))) = 0.10] and normoxic (mild hypercapnic normoxia, FI(O(2)) = 0.21) inspirate challenges in mild hypercapnia (inspired CO(2) fraction = 0.03). First- and second-filial generations and two backcross progeny were also studied to assess response distributions of HVR phenotypes relative to the parental strains. Although the minute ventilation (VE) during hypoxia was comparable between the parental strains, breathing frequency (f) and tidal volume were significantly different; C3 mice demonstrated a slow, deep HVR relative to a rapid, shallow phenotype of B6 mice. The HVR profile in B6C3F(1)/J mice suggested that this offspring class represented a third phenotype, distinguishable from the parental strains. The distribution of HVR among backcross and intercross offspring suggested that the inheritance patterns for f and VE during mild hypercapnic hypoxia are consistent with models that incorporate two genetic determinants. These results further suggest that the quantitative genetic expression of alleles derived from C3 and B6 parental strains interact to significantly attenuate individual HVR in the first- and second-filial generations. In conclusion, the genetic control of HVR in this model was shown to exhibit a relatively simple genetic basis in terms of respiratory timing characteristics.

Acute Disease↗
PubMed1997

Inherited causes of exocrine pancreatic dysfunction.

The exocrine pancreas is functionally immature at birth. Protease function is probably adequate, but lipase activity approximates 5% to 10% of adult values in the newborn and remains low in infancy. Pancreatic amylase secretion is essentially absent at birth and remains low through the first years of life. Functional disturbances of the exocrine pancreas are less frequent in childhood than in adult life. Causes of pancreatic dysfunction in childhood can be divided in two general categories: hereditary conditions, which directly affect the pancreas; and acquired disorders, in which loss of pancreatic function is a secondary phenomenon. Most inherited causes of pancreatic dysfunction are due to a generalized disorder. Cystic fibrosis is, by far, the most common inherited cause of disturbed pancreatic function among Caucasian children. All other inherited causes of exocrine pancreatic dysfunction (eg, Johanson-Blizzard syndrome) are uncommon or rare.

Adult↗
PubMed2005

Ductal lavage of fluid-yielding and non-fluid-yielding ducts in BRCA1 and BRCA2 mutation carriers and other women at high inherited breast cancer risk.

OBJECTIVE: Nipple fluid production and atypical breast duct cells in women at high risk of breast cancer have been associated with further increased risk. Most publications on ductal lavage for cell collection report cannulating fluid-yielding ducts only. We report lavage of fluid-yielding and non-fluid-yielding ducts in women at high inherited breast cancer risk. METHODS: A pilot breast cancer screening study including ductal lavage was conducted in 75 women at high inherited risk, 56 (74.7%) of whom had BRCA1/2 mutations. Ductal lavage was attempted in any duct identifiable with a catheter. RESULTS: Ducts were successfully catheterized in 60 of 75 patients (80%). Successfully catheterized patients were younger (median age 41 versus 53 years, P = 0.0003) and more often premenopausal (51.7% versus 20%, P = 0.041). Thirty-one successfully catheterized patients [51.6%, 95% confidence interval (39.4-63.9%)] had non-fluid-yielding ducts only. Seventeen patients [28.3% (18.5-40.9%)] had atypical cells. Twelve of seventeen [70.6% (46.8-87.2%)] samples with atypia were from non-fluid-yielding ducts. Patients with non-fluid-yielding ducts (versus fluid-yielding ducts) were more likely to have had prior cancer (48.4% versus 17.2%, P = 0.014) or chemotherapy (45.2% versus 17.2%, P = 0.027); this was also true in patients with atypia from non-fluid-yielding ducts. CONCLUSION: Successfully lavaged women were younger and more often premenopausal. Atypical cells can be found in non-fluid-yielding ducts in patients at high inherited breast cancer risk. Non-fluid-yielding ducts, and atypia from non-fluid-yielding ducts, are more common in patients with prior cancer and chemotherapy. Larger studies are needed to identify risk factors and prognostic significance associated with atypia and non-fluid-yielding ducts in high-risk populations, and define their role as biomarkers.

Adult↗
PubMed1999

Genetic maternal effects on human life span through the inheritance of mitochondrial DNA.

Ageing consists of an accumulation of changes with time both at the molecular and cellular levels, accompanying an increased susceptibility to diseases and death. If maternally inherited mitochondrial genes are involved in defining the nature and timing of ageing, and if there are genetic differences in their susceptibility to damage, a maternal contribution could be found in the inheritance of life span. The present study explores the inheritance pattern of longevity and discovers a significant genetic maternal component in human life span.

Adult↗
PubMed1978

Consanguinity in multifactorial inheritance. Application to data on congenital glaucoma.

The increase of parental consanguinity in multifactorial inheritance is evaluated by calculating the expected incidence of affected children whose parents are first cousins, using several values, namely for condition frequency and heritability of liability. This increase is compared to the expected increase in recessive inheritance, when one or more loci are involved. The method is illustrated by examples of recessive and multifactorial conditions and applied, as a test of discrimination between different modes of inheritance, to data on congenital glaucoma.

Consanguinity↗
PubMedDate not supplied

Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene.

Our laboratory recently found a novel mechanism for thrombophilia, which is characterized by an inherited resistance to activated protein C (APC). The APC-resistance test, which measures the anticoagulant response to APC in an activated partial thromboplasin time (APTT) reaction, was devised and used to screen a cohort of consecutive thrombosis patients. APC-resistance was found in approximately 40% of the cases. Other known causes for thrombosis, such as deficiencies of protein C, protein S or antithrombin, were found in another 5% of the patients. Our results, which have recently been confirmed from other laboratories, suggest APC-resistance to be highly prevalent in thrombosis patients. In a majority of cases, APC-resistance was demonstrated to be inherited and family studies revealed an autosomal dominant mode of inheritance. In the investigated families, APC-resistance was associated with thrombosis, which suggests a causal relationship between APC-resistance and thrombosis. An anticoagulant cofactor activity, which corrected APC-resistance, was found in normal plasma, whereas plasma from an individual with pronounced APC-resistance was devoid of this activity. Purification and characterization of the novel APC-cofactor suprisingly revealed that it was identical to coagulation factor V. Thus, factor V is not only an important procoagulant, but also expresses anticoagulant properties as a cofactor to APC. Our present data suggest the anticoagulant function to be a property of unactivated factor V, whereas the procoagulant activity is expressed after activation to Va. APC-resistant individuals have normal levels of procoagulant V-activity, it is now known that APC-resistance is caused by mutation in the factor V gene changing arginine 506 to a glutamine, thus affecting the APC-cleavage site.

Factor V↗
PubMed2004

Long term prognosis of patients with myocardial infarction and normal coronary angiography: impact of inherited coagulation disorders.

The prognosis of patients with myocardial infarction (MI) and normal coronary arteries (NCA) in the presence of an inherited coagulation disorder is unknown. The purpose of this study was to compare the clinical thrombosis outcome of patients with (GpI) or without (GpII), inherited coagulation disorders, who suffered from an acute MI with NCA. Eighty two consecutive patients (mean age 49 +/- 15 years; 29 females) with MI, but NCA, were recruited. Twelve patients (15%) had an inherited coagulation disorder. GpI and GpII were statistically similar regarding age (45 +/- 11 vs 50 +/- 16 years-old), gender (33 vs. 36% female), tobacco consumption (50 vs. 53%), diabetes mellitus (8 vs. 10%), hypertension (25 vs. 17%), obesity (8.3 vs. 14%), family history of coronary heart disease (33 vs. 19%), hypercholesterolemia (50 vs. 21%; p =.08), left ventricular ejection fraction (58 +/- 13 vs. 61 +/- 13%) and spasm (8.3% vs. 17%). All patients were initially treated with antiplatelet agents with the exception of one (8%) in GpI, and 6 (9%) in GpII who were taking oral anticoagulant therapy (ns). The mean follow-up was 57 +/- 26 (range from 2-91 months). During the outcome, 12/78 (15.4%) thrombosis events occurred, including venous thrombosis or pulmonary embolism (1/12 vs. 1/66), reinfarction (2/12 vs. 4/66), and stroke (2/12 vs. 2/66), with two events in one patient (GpI). Kaplan-Meier event-free survival, with combined end-point, defined as venous thrombo-embolic event, reinfarction, or stroke differed between the two groups: 4/12 (33.3%) in GpI and 7/66 (10.6%) in Gp II (p <.02). Patients with MI, NCA and congenital coagulation disorder present a high risk of thrombosis recurrence under antiplatelet agent.

Adult↗
PubMed1997

Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation (Ala223Val MTHFR) in patients with inherited thrombophilic coagulation defects.

To assess whether certain abnormalities of the sulfated amino acid metabolism are associated with the occurrence of thromboembolic events in patients with inherited thrombophilic conditions, the levels of homocyst(e)ine, before or after methionine load, and the presence of the Ala223Val substitution in the 5,10-methylenetetrahydrofolate reductase (MTHFR) were evaluated in 119 subjects with a congenital single thrombophilic condition (type I deficiency of antithrombin n = 10, protein C n = 24, protein S n = 16; activated protein C resistance due to factor V Leiden mutation n = 69). Sixty-three subjects had experienced at least one documented thrombotic event, while the remaining 56 subjects were still free from any thrombotic symptom. Our results show that (1) high homocyst(e)ine levels, either in fasting condition or after methionine load, were not more frequent in subjects with inherited thrombophilic alterations (14.4%) than in normal control subjects (10% by definition) and (2) the frequency of hyperhomocyst(e)inemia was similar in thrombophilic subjects, who already have (14.3%) or have not (14.6%) experienced thrombotic events. As regards the MTHFR mutation, the homozygous condition was present in 23.2% of the thrombophilic patients versus 17.5% in the control subjects, a nonsignificant difference. The mutation was slightly more frequent in those thrombophilic subjects who had suffered a thrombotic episode (25.5%) versus those with no thrombosis (20.8%), with odds ratios of 1.61 (confidence interval (CI) = 0.58-4.52) and 1.24 (CI = 0.42-3.43), respectively. These differences were also nonsignificant. It is concluded that in subjects with inherited thrombophilias, a condition of hyperhomocyst(e)inemia "per se" is not a factor increasing the risk of thrombosis. The risk enhancement conferred by the MTHFR mutation, if any, seems to be slight or limited, and its significance could be ascertained only in a large multicenter trial.

Adult↗
PubMed2000

Transient focal neurological deficits during pregnancy in carriers of inherited thrombophilia.

BACKGROUND AND PURPOSE: The aim of our study was to investigate the association of transient ischemic cerebrovascular events during pregnancy and inherited thrombophilias. METHODS: The study group comprised previously healthy pregnant women who had their first ischemic event during pregnancy (n=12). The control group included 24 healthy women matched with the study women for age, ethnicity, and smoking status. All women were evaluated for factor V Leiden mutation, methylenetetrahydrofolate reductase C677T gene mutation, the G20210A mutation in the prothrombin gene, and deficiencies of plasma proteins C and S and antithrombin III. RESULTS: Inherited thrombophilia was detected in 83% of women with transient neurological manifestations compared with 17% of the control group (P<0.001). CONCLUSIONS: Transient cerebrovascular ischemic events during pregnancy are associated with a high rate of inherited thrombophilias. Pregnant women with focal neurological symptoms should be evaluated for thrombophilia.

Adolescent↗
PubMed1972

Study of four new kindreds with inherited thyroxine-binding globulin abnormalities. Possible mutations of a single gene locus.

Five families with inherited thyroxine-binding globulin (TBG) abnormalities were studied. On the basis of serum thyroxine (T(4))- binding capacity of TBG in affected males, three family types were identified: TBG deficiency, low TBG, and high TBG capacity. In all families evidence for X-linked inheritance was obtained and in one family all criteria establishing this mode of inheritance were met. Only females were heterozygous, exhibiting values intermediate between affected males and normals. Overlap in heterozygotes was most commonly encountered in families with low TBG. QUANTITATIVE VARIATION IN THE SERUM CONCENTRATION OF FUNCTIONALLY NORMAL TBG WAS DEMONSTRATED BY: (a) failure of serum from TBG-deficient subjects to react with anti-TBG antibodies; (b) normal kinetics of T(4) and triiodothyronine-binding to TBG in sera from subjects with low TBG and high TBG capacity; (c) concordance of estimates of TBG concentration by T(4) saturation and by immunological methods; and (d) normal rate of heat inactivation of TBG. No abnormalities in serum transport of cortisol, testosterone, aldosterone, or thyroxine bound to prealbumin could be detected. These observations suggest that all the TBG abnormalities thus far observed reflect mutations at a single X-linked locus involved in the control of TBG synthesis.

Adolescent↗
PubMed1977

Inheritance of low immunoreactive human plasma dopamine-beta-hydroxylase. Radioimmunoassay studies.

Inheritance plays an important role in the determination of human plasma dopamine-beta-hydroxylase (DBH) enzymatic activity. It has been demonstrated that an allele (d) for very low enzymatic plasma DBH is inherited as an autosomal recessive trait. A radioimmunoassay for human DBH was developed to test the hypothesis that the presence of this allele results in a decrease in plasma DBH protein levels. The mean immunoreactive DBH (IDBH) in blood from a randomly selected population of adolescents was 824+/-38 ng/ml (mean+/-SEM, n = 134). The correlation coefficient of enzymatic DBH with IDBH for this group of 134 adolescents was 0.84 (P < 0.001). Of these subjects, 3.7% had values of < 100 ng/ml and appeared to compose a separate subgroup analogous to the 3-4% of the population that is homozygous for the allele for low enzymatic activity. There was a significant sibling-sibling correlation of IDBH values in the 14 sibling pairs included among the 134 subjects studied (r = 0.60, P < 0.025). IDBH was also measured in blood from 56 subjects homozygous (dd) for the allele for low enzymatic DBH (enzymatic activity < 50 U/ml) and in blood of 80 first-degree relatives of homozygous probands. All but two dd subjects had IDBH levels of <100 ng/ml. Results of family studies were compatible with the autosomal recessive inheritance of an allele for IDBH levels of less than 100 ng/ml which segregates with the allele for very low enzymatic activity. Average IDBH in blood of 37 obligate heterozygotes as determined by family studies (Dd) was 599+/-53 ng/ml (mean +/- SEM), significantly lower than the IDBH values found in a randomly selected population (P < 0.005). These results are compatible with the conclusion that the presence of the allele for low plasma enzymatic DBH results in a decrease in the quantity of DBH protein in human plasma.

Adolescent↗
PubMed1978

Inheritance of low serum immunoglobulin D.

Previous studies have shown that log IgD levels in normal individuals are distributed in a nonunimodal manner. Therefore, in this study we tested whether inheritance might play a role in determination of IgD levels. IgD levels were measured in serum or plasma from 301 randomly selected children aged 6-18 yr, 245 consecutive adult blood donors, and 134 first-degree relatives of subjects with low IgD levels. Comparison of serum and plasma from five individuals revealed no difference, so the two were used interchangeably. The distributions of log IgD levels in randomly selected populations of both adults and children were nonunimodal with nadirs at 2.15 IU/ml. In both of these randomly selected populations, 13-14% of the subjects had low IgD values (<2.15 IU/ml). In addition, there was a significant sibling-sibling correlation of log IgD values (r = 0.56, n = 72, P <0.01). Because of the nonunimodality of the frequency distribution histogram for IgD values and because of the familial aggregation of these values, the study was extended to include first-degree relatives of subjects with low plasma IgD. Blood samples from 92% of living first-degree relatives, 134 individuals, were analyzed for their level of IgD, and the results of segregation and pedigree analyses of these data were compatible with autosomal recessive inheritance of an allele for low plasma IgD levels. IgD values in plasma from siblings of probands for low IgD were also non-unimodal in distribution with a nadir at congruent with2.15 IU/ml. The results suggest that there is autosomal recessive inheritance of an allele for low plasma IgD.

Adolescent↗
PubMed1994

Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder.

Recent advances in molecular genetics have revealed the mechanisms underlying a variety of inherited human disorders. Among them, mutations in G protein-coupled receptors have clearly demonstrated two types of abnormalities, namely loss of function and constitutive activation of the receptors. Thromboxane A2 (TXA2) receptor is a member of the family of G protein-coupled receptors and performs an essential role in hemostasis by interacting with TXA2 to induce platelet aggregation. Here we identify a single amino acid substitution (Arg60-->Leu) in the first cytoplasmic loop of the TXA2 receptor in a dominantly inherited bleeding disorder characterized by defective platelet response to TXA2. This mutation was found exclusively in affected members of two unrelated families with the disorder. The mutant receptor expressed in Chinese hamster ovary cells showed decreased agonist-induced second messenger formation despite its normal ligand binding affinities. These results suggest that the Arg60 to Leu mutation is responsible for the disorder. Moreover, dominant inheritance of the disorder suggests the possibility that the mutation produces a dominant negative TXA2 receptor.

Amino Acid Sequence↗
PubMed1994

Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.

Resistance to activated protein C (APC) is the most prevalent inherited cause of venous thrombosis. The APC resistance phenotype is associated with a single point mutation in the factor V gene, changing Arg506 in the APC cleavage site to a Gln. We have investigated 50 Swedish families with inherited APC resistance for this mutation and found it to be present in 47 of them. Perfect cosegregation between a low APC ratio and the presence of mutation was seen in 40 families. In seven families, the co-segregation was not perfect as 12 out of 57 APC-resistant family members were found to lack the mutation. Moreover, in three families with APC resistance, the factor V gene mutation was not found, suggesting another still unidentified cause of inherited APC resistance. Of 308 investigated families members, 146 were normal, 144 heterozygotes, and 18 homozygotes for the factor V gene mutation and there were significant differences in thrombosis-free survival curves between these groups. By age 33 yr, 8% of normals, 20% of heterozygotes, and 40% of homozygotes had had manifestation of venous thrombosis.

Arginine↗
PubMed2000

Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency.

Over 20 severely obese subjects in 11 independent kindreds have been reported to have pathogenic heterozygous mutations in the gene encoding the melanocortin 4 receptor (MC4R), making this the most common known monogenic cause of human obesity. To date, the detailed clinical phenotype of this dominantly inherited disorder has not been defined, and no homozygous subjects have been described. We determined the nucleotide sequence of the entire coding region of the MC4R gene in 243 subjects with severe, early-onset obesity. A novel two-base pair GT insertion in codon 279 was found in two unrelated subjects, and four novel missense mutations, N62S, R165Q, V253I, C271Y, and one mutation (T112M) reported previously were found in five subjects. N62S was found in homozygous form in five children with severe obesity from a consanguineous pedigree. All four heterozygous carriers were nonobese. Several features of the phenotype, e.g. hyperphagia, tendency toward tall stature, hyperinsulinemia, and preserved reproductive function, closely resemble those reported previously in Mc4r knock-out mice. In addition, a marked increase in bone mineral density was seen in all affected subjects. In transient transfection assays, the N62S mutant receptor showed a responsiveness to alphaMSH that was intermediate between the wild-type receptor and mutant receptors carrying nonsense and missense mutations associated with dominantly inherited obesity. Thus MC4R mutations result in a syndrome of hyperphagic obesity in humans that can present with either dominant or recessive patterns of inheritance.

Adolescent↗
PubMed1985

Evidence for autosomal recessive inheritance in 46 families with multiple incidences of autism.

The authors ascertained 46 families with multiple incidences of autism (41 with two and five with three autistic probands). Classical segregation analyses revealed a maximum likelihood estimate of the segregation ratio of p = 0.19 +/- 0.07. This is not significantly less than 0.25, the expected value for autosomal recessive inheritance. However, it is significantly less than 0.50, the expected value for autosomal dominant inheritance. The polygenic threshold model was tested and rejected over a full range of values of heritability and ascertainment probability for these families. These results are most consistent with the hypothesis of autosomal recessive inheritance in this subset of 46 families with multiple incidences of autism.

Adolescent↗
PubMed2003

The PAI-1 gene 4G/5G polymorphism and deep vein thrombosis in patients with inherited thrombophilia.

Genetic and acquired factors may influence phenotypic expression of inherited thrombophilia. Hypofibrinolysis due to excess PAI-1 can be found in patients with deep vein thrombosis (DVT) and 4G/5G polymorphism of the PAI-1 gene may modulate the inhibitor's synthesis. In 149 patients with inherited thrombophilia, the possible thrombotic contribution of both 4G/5G polymorphism and PAI-1 plasma levels was evaluated. Sixty-seven patients with idiopathic DVT and 98 normal subjects were also studied. By comparison with controls, a significantly higher prevalence of 4G/4G genotype was seen in idiopathic DVT and in thrombophilia patients, although in this latter group the difference only remained significant in cases symptomatic for thrombosis (p = 0.01). The 4G/4G genotype was associated with a greater risk of thrombosis both in symptomatic thrombophilia patients (OR 2.85, 95% CI 1.26-6.46) and in idiopathic DVT patients (OR 3.1, 95% CI 1.26-7.59). The greater frequency of 4G allele in symptomatic thrombophilia patients with respect to controls was statistically significant (p = 0.04). Compared to healthy subjects, PAI-1:Ag levels were higher in symptomatic thrombophilia patients and related to the 4G/5G polymorphism, with significantly higher values in the 4G/4G carriers. In conclusion, PAI-1 4G/5G polymorphism may influence PAI-1 expression and thrombotic risk in patients with inherited thrombophilia.

Adolescent↗
PubMed2006

Inherited bone marrow failure syndromes: molecular features.

Recent advances resulting from the identification of the genes responsible for four inherited marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, are reviewed. The interpretation of genetic testing should be guided by an understanding of the limitations of such testing for each disorder. The possibility of an inherited basis for marrow failure must be considered for adults as well as children with aplastic anemia. Shared molecular themes are emerging from functional studies of the genes underlying the different inherited disorders. Genomic instability may result from impaired DNA repair in Fanconi anemia or telomere dysregulation in dyskeratosis congenita. Mutations affecting ribosome assembly or function are associated with Diamond-Blackfan anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome. These findings raise new questions about the molecular mechanisms regulating hematopoiesis and leukemogenesis. Clinical implications arising from these molecular studies are explored.

Anemia, Diamond-Blackfan↗