A common region of 10p deleted in DiGeorge and velocardiofacial syndromes

Daw, S; Taylor, Catherine L.; Kraman, Matthew; Call, Kathy; Mao, Jen-i; Schuffenhauer, Simone; Meitinger, Thomas; Lipson, Tony; Goodship, Judith A.; Scambler, Peter J.

doi:10.1038/ng0896-458

Cited by 195 publications

(116 citation statements)

References 14 publications

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“…36 The deletion map presented here is consistent with this result and further narrows the critical region to a 1 cM interval.…”

Section: Introductionsupporting

confidence: 77%

“…All patients of the present study with features of DGS or VCFS are hemizygous for these two PACs, which define the minimal SRO in the DGS/VCFS patients of this study. Our results refine the DGS2 deletion interval defined and estimated to encompass about 2 Mb by Daw et al, 36 although the exact breakpoints have yet to be determined. The breakpoint in patient LEM narrows the interval by approximately 1 Mb.…”

Section: Critical Dgs2 Regionsupporting

confidence: 71%

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Deletion mapping on chromosome 10p and definition of a critical region for the second DiGeorge syndrome locus (DGS2)

et al. 1998

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DiGeorge syndrome (DGS) is a developmental field defect, characterised by absent/hypoplastic thymus and parathyroid, and conotruncal heart defects, with haploinsufficiency loci at 22q (DGS1) and 10p (DGS2). We performed fluorescence in situ hybridisations (FISH) and polymerase chain reaction (PCR) analyses in 12 patients with 10p deletions, nine of them with features of DGS, and in a familial translocation 10p;14q associated with midline defects. The critical DGS2 region is defined by two DGS patients, and maps within a 1 cM interval including D10S547 and D10S585. The other seven DGS patients are hemizygous for both loci. The breakpoint of the reciprocal translocation 10p;14q maps at a distance of at least 12 cM distal to the critical DGS2 region. Interstitial and terminal deletions described are in the range of 10-50 cM and enable the tentative mapping of loci for ptosis and hearing loss, features which are not part of the DGS clinical spectrum.

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“…36 The deletion map presented here is consistent with this result and further narrows the critical region to a 1 cM interval.…”

Section: Introductionsupporting

confidence: 77%

Section: Critical Dgs2 Regionsupporting

confidence: 71%

Deletion mapping on chromosome 10p and definition of a critical region for the second DiGeorge syndrome locus (DGS2)

et al. 1998

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“…Proplatelet formation is inhibited after either diminished or excessive expression of the transcription factor MafG in megakaryocytes (67), and T cell development in the thymus is blocked when there is either too little or too much GATA3 (32,33,40,68,69). Of note in this regard, the inactivation of one Gata3 allele often results in a mild reduction in T cell development in humans (HDR [hypoparathyroidism, deafness, and renal dysplasia] syndrome) (70)(71)(72) and in mice (49), while a 2-fold increase in the GATA3 protein abundance has been shown to induce T cell lymphoma (73). Here we show that a 2.5-to 5-fold increase in the GATA3 abundance (calculated from the fluorescence intensity), caused at least in part by monoallelic-to-biallelic Gata3 transcriptional activation, regulates allelic exclusion at the Tcrb locus.…”

Section: Discussionmentioning

confidence: 99%

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Sekiguchi

Panwar

et al. 2017

Molecular and Cellular Biology

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Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor ␤ (TCR␤) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCR␤ protein. Here we report that the transgenic overexpression of GATA3 leads predominantly to biallelic TCR␤ gene (Tcrb) recombination. We also found that wild-type immature thymocytes can be separated into distinct populations based on intracellular GATA3 expression and that GATA3 LO cells had almost exclusively recombined only one Tcrb locus (that predicted a functional receptor sequence), while GATA3 HI cells had uniformly recombined both Tcrb alleles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at the Tcrb locus and provide new mechanistic insight into the historic immunological conundrum for how Tcrb allelic exclusion is mediated.KEYWORDS allelic exclusion, T cell receptor beta locus, GATA3, monoallelic-tobiallelic switch O ne enduring mystery in cellular immunology regards the underlying mechanisms that control antigen receptor allelic exclusion (1, 2), the process whereby B or T lymphocytes are programmed to express only one functional allele for each chain of their respective antigen receptors (B cell receptor [BCR] or T cell receptor [TCR]), thus avoiding the coexistence of multiple antigen specificities in a single immune cell. Lymphocytes acquire the diversity of antigen recognition (3) as well as a unique monospecificity for particular antigens (4) during development in the bone marrow (B cells) or the thymus (T cells).T lymphocyte development is generally characterized by division into multiple stages based on developmental timing and the location and expression of specific cell surface markers (5). T cell development begins when multipotential hematopoietic progenitor cells in the bone marrow migrate through the bloodstream to the thymus, where early T lineage progenitors (ETPs) are generated and later specified to become T cells (6-10). ETPs differentiate into double-negative (DN) cells (DN2 to DN4 stages) that express neither the CD4 nor the CD8 coreceptor, then into double-positive (DP)

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“…Others have DG anomaly features and are hemizygous for 10p13. 19 In DG anomaly, the development of thymic tissue is affected; thymic defects occur for ϳ80% of patients, leading to varying degrees of cellular immunodeficiency. 20 DG-SCID describes a small subset of children with clinical features of DG anomaly and severe T-cell immunodeficiency (1-2%) attributable to absent or highly hypoplastic thymic tissue.…”

mentioning

confidence: 99%

Complete DiGeorge Anomaly in the Absence of Neonatal Hypocalcemia and Velofacial and Cardiac Defects

Al‐Tamemi

Mazer

Mitchell³

et al. 2005

Pediatrics

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ABSTRACT. We report an atypical case of complete DiGeorge (DG) anomaly that presented initially exclusively as severe combined immunodeficiency (SCID). The child had severe infections at diagnosis, in keeping with the SCID phenotype; however, normal lymphocyte counts and immunoglobulin levels were noted at admission, which delayed diagnosis. Importantly, the child presented without neonatal hypocalcemia or velofacial or cardiac abnormalities at the time of diagnosis, which masked underlying DG. This case outlines the difficulties in making the diagnosis of SCID in a timely manner and illustrates the variation in presentation of the 22q11.2 deletion syndrome. There should be a high index of suspicion for primary immunodeficiency among children with severe infections and, because management may vary, DG anomaly should be considered in the differential diagnosis of T ؊ B ؉ natural killer ؉ SCID. Severe combined immunodeficiency (SCID) is life-threatening and usually presents in the first few months of life. Common manifestations include failure to thrive, recurrent thrush, and respiratory infections. The hallmark of SCID is absent or poorly functioning T lymphocytes. Although children with SCID often present with lymphopenia, normal or elevated lymphocyte counts are also seen. In addition, normal levels of serum immunoglobulins are often found. 1,2 Therefore, normal lymphocyte counts or immunoglobulin levels should not exclude a diagnosis of primary immunodeficiency (PID) and, among children with recurrent infections, complete evaluation of the immune system, including T, B, and natural killer (NK) cell phenotyping, is required to ensure prompt diagnosis.DiGeorge (DG) anomaly (OMIM 188400) is caused by developmental defects in the third pharyngeal pouch and fourth pharyngeal arch. 3 This disorder is clinically heterogeneous and is characterized by cardiovascular defects and thymic, parathyroid, and craniofacial anomalies. 4,5 Associated problems include esophageal reflux, laryngomalacia, and delay in speech acquisition. Phenotypes range from lifethreatening heart defects or T cell immunodeficiency to mild craniofacial abnormalities and developmental delays. Approximately 80% of DG anomaly cases are caused by a chromosomal deletion generally referred to as del (22)(q11.2q11.2). In fact, 22q11.2 deletion syndrome 6-13 is now used to describe a heterogeneous group of disorders including DG anomaly, velocardiofacial syndrome, 14 and conotruncal anomaly face syndrome and is the most common chromosomal deletion syndrome among humans, occurring with an incidence of ϳ1 case per 3000 live births. 8,11,12,[14][15][16] Among patients with del(22), 90% have a virtually identical 3-megabase heterozygous deletion of 22q11.2 but show great clinical variability, which suggests the presence of additional genetic modifiers. Some patients have DG anomaly features in conjunction with the CHARGE association (association of coloboma, heart defect, agenesis of choanae, retardation of growth or development, genital hypoplasia, and ear an...

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A common region of 10p deleted in DiGeorge and velocardiofacial syndromes

Cited by 195 publications

References 14 publications

Deletion mapping on chromosome 10p and definition of a critical region for the second DiGeorge syndrome locus (DGS2)

Deletion mapping on chromosome 10p and definition of a critical region for the second DiGeorge syndrome locus (DGS2)

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Complete DiGeorge Anomaly in the Absence of Neonatal Hypocalcemia and Velofacial and Cardiac Defects

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