Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients.
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BACKGROUND AND OBJECTIVES: The Italian Gruppo di Studio delle Piastrine recently developed a diagnostic algorithm to assist clinicians in the diagnosis of inherited thrombocytopenias. This algorithm is based on the simplest possible diagnostic investigations and can also be used in centers that are not highly specialized. The aim of the present study was to validate this diagnostic algorithm by applying it to a case series of genetic thrombocytopenias. DESIGN AND METHODS: The diagnostic algorithm was applied retrospectively to 46 consecutive patients observed during the last five years at a single institution. Twenty-eight were affected by defined illnesses or their variants, while 18 had a disorder that did not fit the criteria for any known genetic thrombocytopenia. The study was based on the evaluation of clinical records and laboratory tests. RESULTS: The diagnostic algorithm recognized: 4 homozygous and 4 heterozygous Bernard-Soulier syndromes, 11 MYH9-related diseases, one von WillebrandOs disease type 2B, one gray platelet syndrome and one X-linked thrombocytopenia with thalassemia. Moreover, it identified 4 patients with the clinical and laboratory features of heterozygous Bernard-Soulier syndrome not caused by mutations in the coding region of the GPIbalpha, GPIbbeta, GPIX or GPV genes, and two patients with the clinical phenotype of MYH9-related disease but without MYH9 mutations. Since the diagnostic flow chart did not allow prompt recognition of two subjects with MYH9-related disease, we introduced a small change to the previously proposed flow chart to obviate this defect. INTERPRETATION AND CONCLUSIONS: The diagnostic algorithm correctly diagnosed 26 of 28 patients with known disorders or phenotypic variants of known disorders. By a simple modification of the investigation sequence, its sensitivity reached 100%. The algorithm also identified 18 patients with new, as yet uncharacterized forms of genetic thrombocytopenia. (+info)
Onset of X-linked sideroblastic anemia in the fourth decade.
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We report the case of a 40-year female who manifested late onset, pyridoxine-refractory X-linked sideroblastic anemia, heterozygous for the first described frameshift ALAS2 mutation, CD506-507 (-C). On presentation she had macrocytic anemia with severe iron overload. (+info)
New advances in the DNA damage response network of Fanconi anemia and BRCA proteins. FAAP95 replaces BRCA2 as the true FANCB protein.
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Fanconi anemia (FA) proteins function in a DNA damage response pathway that appears to be part of the network including breast cancer susceptibility gene products, BRCA1 and BRCA2. In response to DNA damage or replication signals, a nuclear FA core complex of at least 6 FA proteins (FANCA, FANCC, FANCE, FANCF, FANCG and FANCL) is activated and leads to monoubiquitination of the downstream FA protein, FANCD2. One puzzling question for this pathway is the role of BRCA2. A previous study has proposed that BRCA2 could be identical to two FA proteins: FANCD1, which functions either downstream or in a parallel pathway; and FANCB, which functions upstream of the FANCD2 monoubiquitination. Now, a new study shows that the real FANCB protein is not BRCA2, but a previously uncharacterized component of the FA core complex, FAAP95, suggesting that BRCA2 does not act upstream of the FA pathway. Interestingly, the newly discovered FANCB gene is X-linked and subject to X-inactivation. The presence of a single active copy of FANCB and its essentiality for a functional FA-BRCA pathway make it a potentially vulnerable component of the cellular machinery that maintains genomic integrity. (+info)
X- and Y-chromosome specific variants of the amelogenin gene allow sex determination in sheep (Ovis aries) and European red deer (Cervus elaphus).
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BACKGROUND: Simple and precise methods for sex determination in animals are a pre-requisite for a number of applications in animal production and forensics. However, some of the existing methods depend only on the detection of Y-chromosome specific sequences. Therefore, the abscence of a signal does not necessarily mean that the sample is of female origin, because experimental errors can also lead to negative results. Thus, the detection of Y- and X-chromosome specific sequences is advantageous. RESULTS: A novel method for sex identification in mammals (sheep, Ovis aries and European red deer, Cervus elaphus) is described, using a polymerase chain reaction (PCR) and sequencing of a part of the amelogenin gene. A partial sequence of the amelogenin gene of sheep and red deer was obtained, which exists on both X and Y chromosomes with a deletion region on the Y chromosome. With a specific pair of primers a DNA fragment of different length between the male and female mammal was amplified. CONCLUSION: PCR amplification using the amelogenin gene primers is useful in sex identification of samples from sheep and red deer and can be applied to DNA analysis of micro samples with small amounts of DNA such as hair roots as well as bones or embryo biopsies. (+info)
Deletions on mouse Yq lead to upregulation of multiple X- and Y-linked transcripts in spermatids.
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Deletions on the mouse Y-chromosome long arm (MSYq) lead to teratozoospermia and in severe cases to infertility. We find that the downstream transcriptional changes in the testis resulting from the loss of MSYq-encoded transcripts involve upregulation of multiple X- and Y-linked spermatid-expressed genes, but not related autosomal genes. Therefore, this indicates that in normal males, there is a specific repression of X and Y (gonosomal) transcription in post-meiotic cells, which depends on MSYq-encoded transcripts. Together with the known sex ratio skew in favour of females in the offspring of fertile MSYqdel males, this strongly suggests the existence of an intragenomic conflict between X- and Y-linked genes. Two potential antagonists in this conflict are the X-linked multicopy gene Xmr and its multicopy MSYq-linked relative Sly, which are upregulated and downregulated, respectively, in the testes of MSYqdel males. Xmr is also expressed during meiotic sex chromosome inactivation (MSCI), indicating a link between the MSCI and the MSYq-dependent gonosomal repression in spermatids. We therefore propose that this repression and MSCI itself are evolutionary adaptations to maintain a normal sex ratio in the face of X/Y antagonism. (+info)
Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth Syndrome.
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The Saccharomyces cerevisiae Taz1 protein is the orthologue of human Tafazzin, a protein that when inactive causes Barth Syndrome (BTHS), a severe inherited X-linked disease. Taz1 is a mitochondrial acyltransferase involved in the remodeling of cardiolipin. We show that Taz1 is an outer mitochondrial membrane protein exposed to the intermembrane space (IMS). Transport of Taz1 into mitochondria depends on the receptor Tom5 of the translocase of the outer membrane (TOM complex) and the small Tim proteins of the IMS, but is independent of the sorting and assembly complex (SAM). TAZ1 deletion in yeast leads to growth defects on nonfermentable carbon sources, indicative of a defect in respiration. Because cardiolipin has been proposed to stabilize supercomplexes of the respiratory chain complexes III and IV, we assess supercomplexes in taz1delta mitochondria and show that these are destabilized in taz1Delta mitochondria. This leads to a selective release of a complex IV monomer from the III2IV2 supercomplex. In addition, assembly analyses of newly imported subunits into complex IV show that incorporation of the complex IV monomer into supercomplexes is affected in taz1Delta mitochondria. We conclude that inactivation of Taz1 affects both assembly and stability of respiratory chain complexes in the inner membrane of mitochondria. (+info)
A method for using incomplete triads to test maternally mediated genetic effects and parent-of-origin effects in relation to a quantitative trait.
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The authors recently developed a semiparametric family-based test for linkage and association between markers and quantitative traits. This quantitative polytomous logistic regression test allows for analysis of families with incomplete information on parental genotype. In addition, it is not necessary to assume normality of the quantitative trait. Previous simulations have shown that the new test is as powerful as the other widely used tests for linkage disequilibrium in relation to a quantitative trait. Here the authors propose an extension to quantitative polytomous logistic regression that allows testing for maternally mediated effects and parent-of-origin effects in the same framework. Missing data on parental genotype are accommodated through an expectation-maximization algorithm approach. Simulations show robustness of the new tests and good power for detecting effects in the presence or absence of offspring effects. Methods are illustrated with birth weight and gestational length, two quantitative outcomes for which data were collected in a Montreal, Canada, study of intrauterine growth restriction between May 1998 and June 2000. (+info)
Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling.
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NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase, is essential for NF-kappaB activation. Mutations disrupting the X-linked NEMO gene cause incontinentia pigmenti (IP), a human genetic disease characterized by male embryonic lethality and by a complex pathology affecting primarily the skin in heterozygous females. The cellular and molecular mechanisms leading to skin lesion pathogenesis in IP patients remain elusive. Here we used epidermis-specific deletion of NEMO in mice to investigate the mechanisms causing the skin pathology in IP. NEMO deletion completely inhibited NF-kappaB activation and sensitized keratinocytes to tumor necrosis factor (TNF)-induced death but did not affect epidermal development. Keratinocyte-restricted NEMO deletion, either constitutive or induced in adult skin, caused inflammatory skin lesions, identifying the NEMO-deficient keratinocyte as the initiating cell type that triggers the skin pathology in IP. Furthermore, genetic ablation of tumor necrosis factor receptor 1 (TNFRI) rescued the skin phenotype demonstrating that TNF signaling is essential for skin lesion pathogenesis in IP. These results identify the NEMO-deficient keratinocyte as a potent initiator of skin inflammation and provide novel insights into the mechanism leading to the pathogenesis of IP. (+info)