Biomedical subjects

Anna Villa

Publications and source records attributed to Anna Villa.

18 recordsLinked to original sources

PubMed2006

Tissue-specific sensitivity to AID expression in transgenic mouse models.

Activation-induced cytidine deaminase (AID), an enzyme with homology to members of the APOBEC family, is involved in somatic hypermutation (SHM) of immunoglobulin (Ig) genes, either by direct deamination of DNA or by an indirect action through its putative RNA editing activity. AID is able to mutate both Ig-like reporter constructs and selected non-Ig genes in normal B cells and in other cells when ectopically overexpressed in mammalian cells and transgenic mice. However, in spite of the fact that in these transgenic animals AID activity was driven by an ubiquitous promoter, only T lymphomas and lung adenomas occurred. In the present work, we constructed three sets of transgenic mice in which AID was under the control of lck, HTLV-I and MMTV promoters, respectively. The lck/AID mice developed thymic lymphomas with variable but high efficiency, while no tumor was detected in HTLV-I/AID mice after two years of monitoring. Four MMTV/AID founder mice died with an atypical clinical picture, although no mammary tumor was found. These findings suggest that additional factors, present in thymocytes but not in other tissues or in lymphoid cells at different stages of differentiation, are needed for AID to fully manifest its tumorigenic potential in mouse. Alternatively, the display of full AID mutagenic and transforming activity could be related to the existence of physiologic DSBs which occur in both thymocytes and switching B cells.

Animals↗

PubMed2006

RAG-dependent primary immunodeficiencies.

Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) cause a spectrum of severe immunodeficiencies ranging from classical T cell-B cell-severe combined immunodeficiency (T(-)B(-)SCID) and Omenn syndrome (OS) to an increasing number of peculiar cases. While it is well established from biochemical data that the specific genetic defect in either of the RAG genes is the first determinant of the clinical presentation, there is also increasing evidence that environmental factors play an important role and can lead to a different phenotypic expression of a given genotype. However, a better understanding of the mechanisms by which the molecular defect impinges on the cellular phenotype of OS is still lacking. Ongoing studies in knock-in mice could better clarify this aspect.

DNA-Binding Proteins↗

PubMed2006

Osteopetroses and immunodeficiencies in humans.

PURPOSE OF REVIEW: This review focuses on human and murine pathologies involving both osteoclasts and immune cells. These diseases have been relevant to the discovery of novel interactions and pathways shared between these two types of cells. RECENT FINDINGS: Interactions between immune cells and osteoclasts were originally shown in murine models by gene targeting of molecules involved in the early steps of osteoclast differentiation, since receptor activator of nuclear factor kappa-B ligand (RANKL), RANK and TNFR-associated factor 6 knockout mice bore abnormalities of both bone resorption and immune system. Subsequently, osteoclast stimulation by RANKL secreted by lymphocytes in autoimmune diseases, such as rheumatoid arthritis, was found. More recently, the identification of immunoreceptor tyrosine-based activation motif receptors and adaptors important for both dendritic cells and osteoclast function has established a link between innate and adaptive immunity and bone. Finally, osteoclasts are also important for hematopoietic stem-cell mobilization, providing a further level of regulation of lymphoid cells. SUMMARY: These findings open up a new field of research, osteoimmunology, which will unravel previously unsuspected links between bone remodelling and the immune response.

Animals↗

PubMed2006

Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement.

UNLABELLED: We report three novel osteopetrosis patients with OSTM1 mutations and review two that have been previously described. Our analysis suggests that OSTM1 defines a new subset of patients with severe central nervous system involvement. This defect is also present in the gl mouse, which could represent a good model to study the role of the gene in the pathogenesis of this disease. INTRODUCTION: Autosomal recessive osteopetrosis (ARO) is a severe hereditary bone disease whose cellular basis is in the osteoclast, but with heterogeneous molecular defects. In addition to the TCIRG1 and the ClCN7 genes, whose mutations account for approximately 55% and 10% of cases, respectively, the OSTM1 gene has been described thus far in only two ARO patients. materials and methods: We report here three novel ARO patients presenting with severe primary central nervous system involvement in addition to the classical stigmata of severe bone sclerosis, growth failure, anemia, thrombocytopenia, and visual impairment with optic atrophy. In addition we analyzed the brain morphology and histology of the grey lethal mutant mouse. RESULTS: The analysis of the OSTM1 gene in two patients, both from Kuwait, showed homozygous two nucleotide deletion in exon 2, leading to a frameshift and premature termination. The third (Lebanese) patient showed a single point mutation in exon 1, leading to a nonsense mutation. The clinical neurological evaluation of the two Kuwaiti patients by CT and MRI scans showed a defect in the white matter, with a specific diagnosis of severe cerebral atrophy. The gl brain showed a diffuse translucent appearance with loss of the normal demarcation between the white and the grey matter, features consistent with myelin loss or hypomyelination. Histological and myelin staining analysis evidenced an atrophy of the corpus callosum with loss of myelin fibers, and in cortical areas, loss of the normal lamination consistent with multiple foci of cortical dysplasia. CONCLUSIONS: These findings suggest that OSTM1-dependent ARO defines a new subset of patients with severe central nervous system involvement leading to a very poor prognosis. The fact that central nervous system involvement is also present in the gl mouse mutant suggests that this mouse is a good model to test possible therapies.

Animals↗

PubMed2005

Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero.

Autosomal recessive osteopetrosis (ARO) is a paradigm for genetic diseases that cause severe, often irreversible, defects before birth. In ARO, osteoclasts cannot remove mineralized cartilage, bone marrow is severely reduced, and bone cannot be remodeled for growth. More than 50% of the patients show defects in the osteoclastic vacuolar-proton-pump subunit, ATP6a3. We treated ATP6a3-deficient mice by in utero heterologous hematopoietic stem cell (HSC) transplant from outbred GFP transgenic mice. Dramatic phenotype rescue by GFP osteoclasts was obtained with engraftment, which was observed in most cases. Engraftment survived for variable periods. Recipients were not immunosuppressed, and graft-versus-host disease was not observed in all pups born after in utero treatment. Thus, differentiation of unmatched HSC transplanted in utero is sufficient to prevent fatal defects in ARO and may prevent complications of ARO unresponsive to conventional bone marrow transplantation. The presence of defective cells is not a barrier to the rescue of the phenotype by donor HSC.

Animals↗

PubMed2005

Polymorphisms of the CLCN7 gene are associated with BMD in women.

UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects. INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population. MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age. RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site. CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

Adult↗

PubMed2005

Vacuolar H+-ATPase d2 subunit: molecular characterization, developmental regulation, and localization to specialized proton pumps in kidney and bone.

The ubiquitous multisubunit vacuolar-type proton pump (H+- or V-ATPase) is essential for acidification of diverse intracellular compartments. It is also present in specialized forms at the plasma membrane of intercalated cells in the distal nephron, where it is required for urine acidification, and in osteoclasts, playing an important role in bone resorption by acid secretion across the ruffled border membrane. It was reported previously that, in human, several of the renal pump's constituent subunits are encoded by genes that are different from those that are ubiquitously expressed. These paralogous proteins may be important in differential functions, targeting or regulation of H+-ATPases. They include the d subunit, where d1 is ubiquitous whereas d2 has a limited tissue expression. This article reports on an investigation of d2. It was first confirmed that in mouse, as in human, kidney and bone are two of the main sites of d2 mRNA expression. d2 mRNA and protein appear later during nephrogenesis than does the ubiquitously expressed E1 subunit. Mouse nephron-segment reverse transcription-PCR revealed detectable mRNA in all segments except thin limb of Henle's loop and distal convoluted tubule. However, with the use of a novel d2-specific antibody, high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern. In human bone, d2 co-localized with the a3 subunit in osteoclasts. This different subunit association in different tissues emphasizes the possibility of the H+-ATPase as a future therapeutic target.

Adult↗

PubMed2005

Damaging-agent sensitivity of Artemis-deficient cell lines.

Defects in repairing double-strand breaks can lead to genome instability and tumorigenesis. In humans, most T(-)B(-) severe combined immunodeficiencies (SCID) have a defect in either the RAG1 or RAG2 gene, are not radiosensitive and do not show genome instability. On the contrary, a minority of T(-)B(-) SCID patients have abnormalities in the Artemis gene and are moderately radiosensitive. Artemis-deficient cells are unable to process hairpin ends after RAG cleavage, but hairpin opening activity alone does not explain the moderate X-ray sensitivity of Artemis-deficient cells. We report here that, at variance with what has been described in mice, cell lines from Artemis(-/-) patients are moderately sensitive to mitomycin C and show only a low to moderate increase in genomic instability, both spontaneously and after exposure to ionizing radiations. There is some heterogeneity in the levels of DNA damage sensitivity and genome instability, which could in part be due to different effects of the specific mutation involved or to genetic background, which may not always represent null alleles. This data supports the hypothesis that, in addition to playing a role in hairpin opening during the V(D)J recombination process, Artemis is involved in the repair of a subset of DNA damage whose exact nature is still undefined.

Animals↗

PubMed2005

Omenn's syndrome occurring in patients without mutations in recombination activating genes.

Omenn syndrome (OS) is characterised by hepatosplenomegaly, lymphadenopathy, erythema, eosinophilia, elevated IgE, oligoclonal T cell expansions and recombinase activating gene (RAG) mutations. We investigated 9 cases of OS to correlate genotype with immunophenotype using a two-color flow cytometry with monoclonal antibodies against CD3 and TCRVB families to map TCRVB usage. T and B clonal cell populations were examined in peripheral blood lymphocytes by PCR and sequencing of TCRB/TCRG T cell and IGH FR2/FR3 B cell products. RAG and Artemis genes were sequenced from genomic DNA. All patients demonstrated absent TCRVB families; six had predominant TCRVB families, six oligoclonal TCR gene rearrangements including TCRGD rearrangements. One demonstrated functional IGH rearrangement, an observation not previously reported. In this clinically homogeneous population, with similar immunological phenotype, RAG mutations were identified in only 2/9 patients. OS is a genetically heterogeneous condition, and patients with similar immunophenotypes may have as yet unidentified gene defects.

Base Sequence↗

PubMed2005

Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage.

Artemis plays a crucial role in the hairpin-opening step of antigen receptor VDJ gene recombination in the presence of catalytic subunit of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs). A defect in Artemis causes human radiosensitive-severe combined immunodeficiency. Cells from Artemis-deficient patients and mice display increased chromosomal instability, but the precise function of this factor in the response to DNA damage remains to be elucidate. In this study, we show that Artemis is hyperphosphorylated in an Ataxia-telangiectasia-mutated (ATM)- and Nijmegen breakage syndrome 1 (Nbs1)-dependent manner in response to ionizing radiation (IR), and that S645 is an SQ/TQ site that contributes to retarded mobility of Artemis upon IR. The hyperphosphorylation of Artemis is markedly reduced in ATM- and Nbs1-null cells. Reintroduction of wild-type ATM or Nbs1 reconstituted Artemis hyperphosphorylation in ATM- or Nbs1-deficient cells, respectively. In support of this functional link, hyperphosphorylated Artemis was found to physically associate with the Mre11/Rad50/Nbs1 complex in an ATM-dependent manner in response to IR-induced DNA double strand breaks (DSB). Since deficiency of either DNA-Pkcs or ATM leads to defective repair of IR-induced DSB, our finding places Artemis at the signaling crossroads downstream of DNA-PKcs and ATM in IR-induced DSB repair.

Ataxia Telangiectasia↗

PubMed2005

AIRE deficiency in thymus of 2 patients with Omenn syndrome.

Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.

Animals↗

PubMed2004

In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects.

UNLABELLED: We studied osteoclastic differentiation from normal and osteopetrotic human CD14 cells in vitro. Defects in acid transport, organic matrix removal, and cell fusion with deficient attachment were found. Analysis of genotypes showed that TCIRG1 anomalies correlated with acid transport defects, but surprisingly, organic matrix removal failure correlated with CLCN7 defects; an attachment defect had normal TCIRG1 and CLCN7. INTRODUCTION: Osteopetrotic subjects usually have normal macrophage activity, and despite identification of genetic defects associated with osteopetrosis, the specific developmental and biochemical defects in most cases are unclear. Indeed, patients with identical genotypes often have different clinical courses. We classified defects in osteoclast differentiation in vitro using four osteopetrotic subjects without immune or platelet defects, three of them severe infantile cases, compared with normals. MATERIALS AND METHODS: Osteoclast differentiation used isolated CD14 cells; results were correlated with independent analysis of two key genes, CLCN7 and TCIRG1. CD14 cell attachment and cell surface markers and extent of differentiation in RANKL and colony-stimulating factor (CSF)-1 were studied using acid secretion, bone pitting, enzyme, and attachment proteins assays. RESULTS AND CONCLUSIONS: CD14 cells from all subjects had similar lysosomal and nonspecific esterase activity. With the exception of cells from one osteopetrotic subject, CD14 cells from osteopetrotic and control monocytes attached similarly to bone or tissue culture substrate. Cells from one osteopetrotic subject, with normal CLCN7 and TCIRG1, did not attach to bone, did not multinucleate, and formed no podosomes or actin rings in RANKL and CSF-1. Attachment defects are described in osteopetrosis, most commonly mild osteopetrosis with Glantzman's thrombasthenia. However, this case, with abnormal integrin alphavbeta3 aggregates and no osteoclasts, seems to be unique. Two subjects were compound heterozygotes for TCIRG1 defects; both had CD14 cells that attached to bone but did not acidify attachments; cell fusion and attachment occurred, however, in RANKL and CSF-1. This is consistent with TCIRG1, essential for H+-ATPase assembly at the ruffled border. A compound heterozygote for CLCN7 defects had CD14 cells that fused in vitro, attached to bone, and secreted acid, TRACP, and cathepsin K. However, lacunae were shallow and retained demineralized matrix. This suggests that CLCN7 may not limit H+-ATPase activity as hypothesized, but may be involved in control of organic matrix degradation or removal.

Acid Phosphatase↗

PubMed2004

TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA.

Human malignant infantile osteopetrosis (arOP) is a genetically heterogeneous autosomal recessive disorder of bone metabolism. The TCIRG1 gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, is responsible for more than one-half of the arOP patients. We performed genetic analysis of TCIRG1 in 55 arOP patients including 25 new cases and identified nine novel mutations. The two most frequent mutations, c.1674-1G>A (aberrant splicing: r.1674_1884del) and c.2005C>T (protein variation: p.Arg669X), found in 17 and 16 alleles, respectively, constituted 30% of all TCIRG1 abnormalities. They both originated in Northern Europe, p.Arg669X quite recently from West Flanders, Belgium. As substitutions in splicing regulatory sequences represented a large portion (40%; 44 alleles) of the TCIRG1 variations, we developed a functional splicing assay to distinguish between polymorphic variants and disease-causing mutations. Three intronic nucleotide substitutions flanking the splice sites (c.117+4A>T; c.1673+5G>A; and c.504-8G>A) were studied using hybrid minigenes and an abnormal processing of the transcripts was demonstrated in all cases. Cotransfection experiments with complementary U1 snRNAs performed in c.117+4A>T and c.1673+5G>A mutations showed that only in the first case was the defect at the 5' splice site corrected, indicating that mutations near the invariant GT donor sites are mechanistically different. These findings indicate the feasibility of the hybrid minigene approach to detect splicing defects, particularly in patients in whom the RNA is not available. In addition, the present results suggest that modified U1 snRNAs may represent a new therapeutic strategy for arOP patients with a U1 snRNP-dependent splicing defect.

Alternative Splicing↗

PubMed2003

Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts.

The relative contribution of aneuploidy and gene mutations to human tumorigenesis is not yet known. Studies in mice have demonstrated that even single point mutations in oncogenes and tumor suppressor genes can dramatically increase tumor frequency. However, models to evaluate the definitive role of aneuploidy and genomic instability are not yet available. Human fibroblast cells have long been used as a tool for investigating proliferation, senescence, immortalization, and tumorigenesis, all processes that are strongly interrelated. We have now used antisense and ribozyme-mediated temporary inhibition of BUB1 to study the consequences of mitotic checkpoint failure on the development of aneuploidy. The analysis of cell colonies selected by soft agar growth showed evidence of chromosome instability and delayed senescence, without being tumorigenic in nude mice. Our data suggest that chromosomal instability and aneuploidy are early changes that precede tumorigenicity in the multistep process leading to neoplastic transformation.

Aneuploidy↗

PubMed2003

Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human.

The spontaneous mouse grey-lethal (gl) mutation is responsible for a coat color defect and for the development of the most severe autosomal recessive form of osteopetrosis. Using a positional cloning approach, we have mapped and isolated the gl locus from a approximately 1.5 cM genetic interval. The gl locus was identified in a bacterial artificial chromosome (BAC) contig by functional genetic complementation in transgenic mice. Genomic sequence analysis revealed that the gl mutation is a deletion resulting in complete loss of function. The unique approximately 3 kb wild-type transcript is expressed primarily in osteoclasts and melanocytes as well as in brain, kidney, thymus and spleen. The gl gene is predicted to encode a 338-amino acid type I transmembrane protein that localizes to the intracellular compartment. Mutation in the human GL gene leads to severe recessive osteopetrosis. Our studies show that mouse Gl protein function is absolutely required for osteoclast and melanocyte maturation and function.

Amino Acid Sequence↗

PubMed2003

Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis.

Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. Podosomes, alphaVbeta3 receptor, c-Src, and PYK2 were unremarkable. Consistent with the finding in the bone biopsies, these cells excavated pits faintly stained with toluidine blue, indicating inefficient bone resorption. Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity.

Acid Phosphatase↗

PubMed2003

Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis.

UNLABELLED: Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family. INTRODUCTION: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown. MATERIALS AND METHODS: In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters. RESULTS AND CONCLUSIONS: In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation, including two brothers from a large family with a history of ADO-II in which the presence of a second ClCN7 mutation was formally excluded. Despite an early and severe clinical presentation, these five patients all reached adulthood, suggesting that the degree of dominant interference with chloride channel function can vary widely. Our findings suggest that recessive ClCN7-dependent ARO may be associated with CNS involvement and have a very poor prognosis, whereas heterozygous ClCN7 mutations cause a wide range of phenotypes even in the same family, ranging from early severe to nearly asymptomatic forms. These findings have prognostic implications, might complicate prenatal diagnosis of human osteopetroses, and could be relevant to the management of these patients.

Adolescent↗

PubMed2002

Omenn syndrome in the context of other B cell-negative severe combined immunodeficiencies.

Severe combined immunodeficiencies represent a heterogeneous group of hereditary defects of the immune system that affect both T and B cells and whose etiology has only recently begun to be understood. A portion of these SCID patients bear a defect in either of the two recombination-activating genes, Rag-1 or Rag-2, while others have mutations in a newly identified gene, Artemis. Omenn syndrome is an unusual severe immunodeficiency with T cells but no B cells, and peculiar features also due to a defect in Rag-1 or Rag-2 genes. All these three forms are characterized by an impairment of the VDJ recombination, the process that insures the somatic diversification of immunoglobulin and T cell receptor-encoding genes. Recent findings have enabled us to better understand the pathophysiology of these three immunodeficiencies, which affect the V(D)J recombination process to a different extent and in different ways.

B-Lymphocytes↗