Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome

X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein-Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.

Physical map and cosmid contig encompassing a new interstitial deletion of the X-linked lymphoproliferative syndrome region

The X-linked lymphoproliferative syndrome (XLP) is an inherited immuno-deficiency to Epstein-Barr virus infection that has been mapped to chromosome Xq25. Molecular analysis of XLP patients from ten different families identified a small interstitial constitutional deletion in 1 patient (XLP-D). This deletion, initially defined by a single marker, DF83, known to map to interval Xq24-q26.1, is nested within a previously reported and much larger deletion in another XLP patient (XLP-739). A cosmid minilibrary was constructed from a single mega-YAC and used to establish a contig encompassing the whole XLP-D deletion and a portion of the XLP-739 deletion. Based on this contig, the size of the XLP-D deletion can be estimated at 130 kb. The identification of this minimal deletion, within which at least a portion of the XLP gene is likely to reside, should greatly facilitate efforts in isolating the gene.

Mandibulofacial Syndrome With Growth and Mental Retardation, Microcephaly, Ear Anomalies With Skin Tags, and Cleft Palate in a Mother and Her Son: Autosomal Dominant or X-Linked Syndrome?

We report on a Brazilian mother and her son affected with mandibulofacial dysostosis, growth and mental retardation, microcephaly, first branchial arch anomalies, and cleft palate. To date only three males and one female, all sporadic cases, with a similar condition have been reported. This article describes the first familial case with this rare condition indicating autosomal dominant or X-linked inheritance. (C) 2009 Wiley-Liss, Inc.

X monosomy and balanced Robertsonian translocation in a girl with Turner Syndrome

We describe a case of X monosomy associated with a maternally inherited t(13;14) Robertsonian translocation in a girl with Turner syndrome. The girl's X chromosome was demonstrated to be maternally inherited, ruling out the hypothesis that the translocation exerted an interchromosomal effect on the origin of the monosomy. Chromosomes 13 and 14 showed biparental inheritance.

Genomic profile of a Li-Fraumeni-like syndrome patient with a 45,X/46,XX karyotype, presenting neither mutations in TP53 nor clinical stigmata of Turner syndrome

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.

Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome

X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein–Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.

Cardiac syndrome X: relevance of arterial pressure waveform analysis to patients with chest pain and normal coronary arteries

We report the case study of a 68-year-old female with cardiac syndrome X presenting with abnormal pressure waveforms and a hypertensive response to exercise with ST-segment depression. After amlodipine treatment, pressure waveform morphology was significantly improved, exercise testing was normal and symptoms had resolved. This case emphasizes the potential clinical value of arterial waveform analysis.

Assessing the immune phenotype of cardiac syndrome x: a prospective study of biomarkers

Cardiac Syndrome X (CSX), the presence of angina pectoris with objective signs of myocardial ischaemia despite angiographically normal epicardial coronary arteries, appears to be due to coronary microvascular dysfunction and is known to be associated with an elevation of several inflammatory biomarkers, suggesting a possible role for inflammation in its pathogenesis. We aimed to further characterise this relationship by prospectively analysing a wide variety of molecular biomarkers in a cohort of CSX patients thereby charting the changes in biomarkers throughout the natural history of CSX from its initial diagnosis to eventual disease quiescence. We found that CSX patients, when compared to healthy controls, have a persistent low-grade systemic inflammatory response characterised by an elevation of Tumour Necrosis Factor and Interferon-gamma, regardless of the presence of contemporaneous signs or symptoms of disease activity. Interleukin-6 and C-reactive Protein (CRP) are only elevated when patients have clinical evidence of disease activity and may be state markers in CSX. Moreover, CRP levels appear to correlate with signals of disease severity such as the time taken to develop symptoms during exercise stress testing. We have also demonstrated that the enzyme Indoleamine-2,3- dioxygenase is upregulated in active disease thus providing a possible explanation for the increased burden of psychological disease encountered in CSX. Analysis of the microRNA transcriptome showed that miR-143 is significantly under-expressed in CSX patients. This could allow phenotype switching in vascular smooth muscle cells with the resultant vascular remodelling causing reduced vessel responsiveness to local rheological stimuli and reduced luminal diameter with consequent increased microvascular resistance during times of increased myocardial oxygen demand, thereby limiting maximal hyperaemia during exercise. Our findings corroborate many previous hypotheses regarding the role of inflammation in CSX, generate new insights into possible pathogenic mechanisms and offer new therapeutic targets for the future management of this important cardiological condition.

A longitudinal study of motivation and competence in children with Down syndrome : early childhood to early adolescence

Background Motivation has been identified as an area of difficulty for children with Down syndrome. Although individual differences in mastery motivation are presumed to have implications for subsequent competence, few longitudinal studies have addressed the stability of motivation and the predictive validity of early measures for later academic achievement, especially in atypical populations. Method The participants were 25 children with Down syndrome. Mastery motivation, operationalised as persistence, was measured in early childhood and adolescence using tasks and parent report. At the older age, preference for challenge, another aspect of mastery motivation, was also measured and the children completed assessments of academic competence. Results There were significant concurrent correlations among measures of persistence at both ages, and early task persistence was associated with later persistence. Persistence in early childhood was related to academic competence in adolescence, even when the effects of cognitive ability at the younger age were controlled. Conclusions For children with Down syndrome, persistence appears to be an individual characteristic that is relatively stable from early childhood to early adolescence. The finding that early mastery motivation is significant for later achievement has important implications for the focus of early interventions.