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Mutations in GARS cause dominantly inherited neuropathies in humans. GARS encodes glycyl-tRNA synthetase, the enzyme that couples glycine to its tRNA. In this issue of Neuron, Seburn et al. have identified and characterized a mutant mouse with a dominantly inherited axonal neuropathy caused by a Gars mutation that is inferred to have a gain of function.
Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, delayed muscle relaxation after contraction (pseudomyotonia), and hyperhidrosis, associated with well described spontaneous electromyographic features. It is usually an acquired disorder associated with autoantibodies against neuronal voltage-gated potassium channels. However, mutations of KCNA1, encoding the K(+) channel subunit hKv1.1, have been reported in rare families with neuromyotonia, and mutations in KCNQ2, encoding voltage-gated potassium M channel subunit, in families with benign neonatal seizures and myokymia. We report a three-generation family with inherited neuromyotonia without evidence of immunological involvement. Genetic study excluded mutations in KCNA1, KCNA2, KCNA6 and KCNQ2 genes. Our study does not completely exclude the involvement of other genes encoding ion channels subunits in the pathogenesis of this disorder. Further studies of familial cases will shed light on the molecular basis of inherited neuromyotonia.
In the last few years, major advancement has been made in the understanding of the genetic basis of inherited arrhythmogenic diseases. Interestingly, the information obtained with the application of molecular genetics to these diseases is now influencing their clinical management, allowing gene-specific risk stratification and gene-specific management. The first attempt for a gene-specific therapy was made in 1995 with the use of mexiletine in long-QT syndrome (LQTS) patients with mutations in the SCN5A gene. Since then, several investigators have proposed novel therapeutic approaches based on the identification of the functional consequences of genetic mutations. In some instances, these novel therapies have already been introduced in clinical practice, and data are being collected to establish their long-term efficacy. In this review, we will summarize the current understanding of the molecular bases of inherited arrhythmias, with a specific focus toward discussing the most recent advancements toward the development of gene-specific therapies.
INTRODUCTION: Inherited giant platelet disorders (IGPD) are a heterogeneous group of rare diseases characterized by thrombocytopenia, large platelets and variable bleeding symptoms. Glycoprotein (GP) expression on platelet surface in these conditions is poorly characterized. We have investigated the expression of constitutively expressed platelet membrane GP and the response to TRAP activation in a group of patients with different forms of inherited macrothrombocytopenias. MATERIALS AND METHODS: Two patients diagnosed Epstein syndrome (ES), two with Bernard-Soulier syndrome (BSS) and eight with Mediterranean macrothrombocytopenia (MM) were studied using flow cytometry combined to monoclonal antibodies (MoAbs). Mean platelet volume was also measured. RESULTS: In general, there was an increase in the binding of MoAbs directed against platelet membrane GPs in the patients studied (except, obviously, in BSS patients). The observed increase ranged between 0.9 and 3.36 times the value of the control for GPIbalpha, between 1.36 and 7.2 times for GPIIb-IIIa and 0.94 and 8.07 times for GPIV. However, when the observed value was divided by the measured platelet volume, the estimated density was similar to controls in the case of GPIbalpha but were increased for GPIIb-IIIa and GPIV. TRAP activation provoked significant increments in the number of copies of GPIIb-IIIa complexes present on platelet surface in controls (91%), MM patients (49%), but almost no changes in BSS platelets (6%). CONCLUSION: In the group of macrothrombocytopenia studied, an increase in the expression of platelet membrane GP was observed, although a wide variability exists even in patients with the same disorder.
Inherited platelet cyclo-oxygenase (COX) deficiency is a rare bleeding disorder. We report here the first case of familial type 2 platelet COX deficiency responsible for a moderate bleeding phenotype. The propositus was admitted in the emergency department for major epistaxis following treatment with aspirin. Epinephrine closure time is very sensitive to drugs which inhibit COX but the test was normal in patients with inherited COX deficiency. This clinical and biological data suggest that the anti-platelet effect of aspirin may be dependent on mechanisms other than the inhibition of COX. Thrombin generation test confirmed mild bleeding phenotype in patients with COX deficiency as they had normal thrombin generating capacity.
We analysed the systematic environmental influences and the additive genetic variation for the presumed inherited eye diseases (PIED), membrana pupillaris persistens, distichiasis, primary lens luxation, non-congenital cataract, and progressive retinal atrophy, in Tibetan Terriers. Data were obtained from the International Kennel Club for Tibetan dog breeds in Germany. PIED were recorded in the years 1987 to 2001 by standardised protocols of the Dortmunder Kreis, the association for diagnosis of inherited eye diseases in animals (DOK). The material included 849 Tibetan Terriers from 596 litters in 203 different kennels. The multivariate linear animal model using residual maximum likelihood methods regarded the fixed effects of sex, birth year, experience of the veterinary ophthalmologist, litter size, percentage of examined dogs per litter, inbreeding coefficient, and age at examination. The common environment of the litter and the additive genetic effect of the animal were taken into account as randomly distributed effects. The heritability estimates for PIED in Tibetan Terriers were h2=0.17+/-0.04 (membrana pupillaris persistens), h2=0.04+/-0.03 (distichiasis), h2=0.13+/-0.04 (primary lens luxation), h2=0.13+/-0.04 (non-congenital cataract), and h2=0.49+/-0.08 (progressive retinal atrophy). The additive genetic correlation between non-congenital cataract and progressive retinal atrophy was highly positive rg=0.76+/-0.11, while that between membrana pupillaris persistens and progressive retinal atrophy rg=-0.43+/-0.14 was highly negative. The number of examinations performed by the veterinary ophthalmologists was associated with higher heritabilities for non-congenital cataract and progressive retinal atrophy. We concluded from our analysis that all investigated PIED in Tibetan Terriers are genetically influenced.
The transovarial transmission of two species of begomovirus, Tomato yellow leaf curl virus (TYLCV) and Tomato yellow leaf curl Sardinia virus (TYLCSV), through generations of Bemisia tabaci of the B and Q biotypes has been investigated. Different life stages of the progeny of viruliferous female whiteflies have been analysed by PCR detection of viral DNA and infectivity tests. Our results indicate that TYLCSV DNA can be detected in eggs and nymphs, and to a lesser extent adults, of the first-generation progeny. Infectivity tests using a large number of adult progeny of the first, second, and third generation indicate that even when viral DNA is inherited, infectivity is not. For TYLCV, neither viral DNA nor infectivity were associated with the progeny of viruliferous female whiteflies. Because the inherited viral DNA is unable to give rise to infections, the transovarial transmission of TYLCSV DNA appears to have no epidemiological relevance.
In most animals, fertilized eggs inherit one centrosome from a meiosis-II spindle of oocytes and another centrosome from the sperm. However, since first proposed by Boveri [Sitzungsber. Ges. Morph. Phys. Münch. 3 (1887) 151-164] at the turn of the last century, it has been believed that only the paternal (sperm) centrosome provides the division poles for mitosis in animal zygotes. This uniparental (paternal) inheritance of centrosomes is logically based on the premise that the maternal (egg) centrosome is lost before the onset of the first mitosis. For the processes of the selective loss of the maternal centrosome, three models have been proposed: One stresses the intrinsic factors within the centrosome itself; the other two emphasize external factors such as cytoplasmic conditions or the sperm centrosome. In the present study, we have examined the validity of one of the models in which the sperm centrosome overwhelms the maternal centrosomes. Because centrosomes cast off into both the first and the second polar bodies (PB) are known to retain the capacity for reproduction and cell-division pole formation, we observed the behavior of those PB centrosomes with reproductive capacity and the sperm centrosome in the same zygotic cytoplasm. We prepared two kinds of fertilized eggs that contain reproductive maternal centrosomes, (1) by micromanipulative transplantation of the PB centrosomes into fertilized eggs, and (2) by suppression of the PB extrusions of fertilized eggs with cytochalasin B. In both types of eggs, the PB centrosomes could double and form cell-division poles, indicating that they are not suppressed by the sperm centrosome, which in turn indicates that selective loss of the maternal centrosome is due to intrinsic factors within the centrosomes themselves.
Allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning regimens has been an effective treatment for many patients with hematologic malignancies or inherited blood disorders. Unfortunately, such regimens have been associated with significant toxicity, limiting their use to otherwise healthy, relatively young patients. In an attempt to extend treatment by allogeneic HCT to older patients and those with comorbid conditions, several groups of investigators have developed reduced-intensity or truly nonmyeloablative conditioning regimens, lacking such toxicity. Analogous to conventional regimens, reduced-intensity regimens both eliminated host-versus-graft (rejection) reactions and produced major anti-tumor effects. In contrast, nonmyeloablative regimens have relied on optimizing both pre-and posttransplant immunosuppression to overcome host-versus-graft reactions, while anti-tumor responses have depended mainly on immune-mediated graft-versus-tumor effects. In this review, we define reduced-intensity and truly nonmyeloablative regimens, describe the preclinical development and clinical application of a very low intensity nonmyeloablative regimen, and review results with reduced-intensity regimens in patients with hematologic malignancies or inherited blood disorders.
Inherited coagulation protein deficiencies associated with bleeding diatheses may present with spontaneous bleeding early in life, or may not be recognized until the development of hemorrhage after trauma or surgery. Diagnostic evaluation with coagulation screening tests, followed by confirmation with coagulation factor assays, is essential for appropriate management. For moderate-to-severe hemophilia, treatment includes coagulation factor replacement with purified, plasma-derived coagulation factor, or in the case of hemophilia A, factor VIII concentrate produced with recombinant techniques. Increased use of pharmacologic agents such as desmopressin acetate for patients with mild hemophilia A or type 1 von Willebrand's disease has allowed physicians to treat patients without the risk of infectious complications from plasma-derived factor concentrates. In addition to the management of the inherited bleeding disorders, patients may also require management of human immunodeficiency virus infection, hepatitis, and coagulation factor inhibitors. Issues for the coming years will include continued work to ensure product safety, the role of prophylactic treatment to prevent longterm disabilities, and the application of gene therapy to the management of bleeding disorders.
PURPOSE: To report the familial occurrence of optic pits and to screen the candidate PAX2 gene for mutations in this family. METHODS: Clinical family study. Standard mutation analysis of the PAX2 exons. RESULTS: Unilateral optic pits were present in three generations of one family and were inherited in an autosomal dominant fashion. No mutations in the PAX2 gene, responsible for the renal-optic coloboma syndrome, were found. CONCLUSION: Unilateral optic pits may be inherited in an autosomal dominant fashion and not in association with mutation in the PAX2 gene.
OBJECTIVE: Delayed afterdepolarization-induced triggered activity originating in ventricular myocardium is a mechanism for some age-dependent, inherited ventricular tachycardias in a colony of German shepherd dogs. METHODS: We used standard microelectrode techniques to study beta-adrenergic receptor subtype modulation of the triggered activity in anteroseptal left ventricular myocardium from eleven of these dogs and seven unafflicted, age-matched German shepherd controls. RESULTS: During sustained stimulation at cycle lengths of 300-4000 ms, 10(-9)-10(-7) M isoproterenol concentration-dependently shortened action potential duration (APD) to 90% repolarization more in myocardium from afflicted than from unafflicted dogs. This shortening was prevented by a beta(1)-blocker CGP20712A (10(-7) M) while a beta(2)-blocker ICI118551 (10(-7) M) did not modify the effect of isoproterenol in either group. The beta(2)-agonist zinterol 10(-8)-10(-6) M had no effect on APD. Stimulation at a cycle length of 250 ms in the presence of 10(-7) M isoproterenol induced more triggered AP in myocardium from afflicted than unafflicted dogs. beta(1)-Blockade completely eliminated, while beta(2)-blockade facilitated, and the beta(2)-agonist zinterol did not induce triggered activity in the two groups. CONCLUSION: Isoproterenol effects on APD and triggered activity in the myocardium of dogs with inherited arrhythmias are due primarily to an abnormality of beta(1)-adrenoceptor mediated signaling that is subject to beta(2)-adrenergic modulation.
The inherited disorders of rd mice and affected Irish setter dogs are characterized by the accumulation of cyclic GMP (cGMP). Since the cGMP level in normal retinal rods is regulated by a light-activated enzyme cascade involving rhodopsin, transducin, and phosphodiesterase, an abnormality associated with any of these three proteins would cause cGMP accumulation. In order to determine the relationship between different forms of retinal degeneration and the transducin content in the affected retinas, affinity-purified antibodies directed against the individual subunits of bovine transducin were prepared. These antibodies, which recognized transducin in many vertebrate species, were used to compare the retinal content of this protein at various stages of inherited photoreceptor degeneration. In each of the disorders studied (rd and rds mice, RCS rat, and affected Irish setter dog), retinas at early stages of degeneration displayed two characteristics similar to those of normal control retinas. First, all three subunits of transducin were detected and found to have normal electrophoretic mobility, suggesting that these disorders are unlikely to be due to changes in the composition of transducin subunits. Second, the amount of cross-reactive T beta always exceeded those of T alpha and T gamma. This disproportionately higher amount of T beta-like protein became more pronounced as the visual cells degenerated. In retinas which had undergone complete photoreceptor degeneration, cross-reactive T alpha and T gamma were undetectable. In contrast, anti-T beta gamma antibodies detected an amount of T beta-like polypeptide corresponding to 10-25% of the control. Since our anti-T beta gamma antibodies recognize the beta subunit of the GTP-binding N proteins of the adenylate cyclase system, this finding suggests that this residual T beta-like protein, which is not part of transducin, may be associated with other GTP-binding regulatory proteins.
Familial hypertrophic cardiomyopathy (HCM) has been defined as a disease of the cardiac sarcomere, although sarcomeric protein mutations are not found in one third of cases. We have recently shown that HCM associated with Wolff-Parkinson-White syndrome (WPW) and conduction disease can be caused by mutations in PRKAG2, which encodes the gamma2 subunit of AMPK, an enzyme central to cellular energy homeostasis. AMPK is a heterotrimer composed of one catalytic subunit (alpha) and two regulatory subunits (beta and gamma). Seven known genes encode the subunit isoforms (alpha1, alpha2, beta1, beta2, gamma1, gamma2, gamma3) and all are expressed in the heart. To better understand the role of AMPK mutations in HCM/WPW and other inherited cardiomyophathies, all 7 subunit genes were screened for mutations in a panel of probands: 3 with HCM/WPW, 4 with DCM/WPW, 38 with HCM alone (in whom contractile protein mutations had not been found) and 13 with DCM alone. In total, 73 amplimers were screened in the 58 probands and a number of polymorphisms, including non-conservative substitutions, were identified. However, no further disease-causing mutations were found in any AMPK subunit gene. These results indicate that HCM with WPW is a distinct, but genetically heterogeneous, condition caused by mutations in PRKAG2 and in an unknown gene or genes, not involved in the AMPK complex. Mutations in PRKAG2 appear to specifically cause HCM with WPW and conduction disease, and not other inherited cardiomyopathies. As deleterious alleles were not found in other AMPK subunit isoforms, the mutations affecting PRKAG2 are likely to confer a specific alteration of AMPK function of particular importance in the myocardium.
Prominent physical features of the Aarskog syndrome are short stature, telecanthus, ptosis, short broad nose, long philtrum, thin upper vermilion border and pouty lower lip, low-set jug-handle ears, short broad hands with clawlike positioning of the fingers, broad feet with bulbous toes, ventral scrotal folds, cryptorchidism, and hernias. Four families with 20 affected males are reported. Pedigree analysis is compatible with X-linked recessive inheritance with occasional partial expression in heterozygote females. The fact that seven sons, all unaffected, have been born to affected males argues against the alternative hypothesis of autosomal sex-influenced inheritance.
Selected immunologic functions were assessed in 14 patients with the Shwachman syndrome. Nine patients were neutropenic and four had low levels of IgA or of IgM. Neutrophil mobility was significantly defective in the group of patients as a whole (in 12 it was below the lower limit of normal) and in their parents. No other consistent abnormality in immunity was found. These results suggest that the defective neutrophil mobility is a feature of Shwachman syndrome which may contribute to the vulnerability of these patients to frequent infections. The defect appears to be a primary genetic one, inherited as an autosomal recessive characteristic consistent with the assumed inheritance of Shwachman syndrome.
The inheritance pattern of the exstrophy-epispadias complex was investigated by a combined literature review and a survey of the personal experience of pediatric urologists in North and South America, and Europe. Bladder exstrophy recurred in only 9 of approximately 2,500 families (1 in 275) with bladder exstrophy or complete epispadias. The recurrence of the exstrophy-epispadias complex in offspring of parents with bladder exstrophy or complete epispadias has never been described previously. We identified 215 offspring produced by parents with bladder exstrophy or epispadias, and bladder exstrophy was inherited in 3 of the offspring (1 in 70 live births). The recurrence of bladder exstrophy in offspring of parents with the exstrophy-epispadias complex is greater than previously assumed.
Urological procedures pose specific medical and surgical problems in the patient with a hemorrhagic disorder. Three men, each with a different inherited deficiency involving the factor VIII molecule, underwent prostatectomy. Prolonged postoperative genitourinary hemorrhage was encountered and treated with replacement therapy and the use of inhibitors of fibrinolysis. Successful management of these patients with inherited coagulopathies depends on a thorough understanding of the hemostatic defect, adequate laboratory support and sufficient supplies of blood products.