Background
Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections ...caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations).
Aim
To study the mutation spectrum in ICF syndrome.
Materials and methods
Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members.
Results
We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta‐analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients.
Discussion
The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort.
Conclusion
Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Introduction In 9–17% of Wilms tumour patients a predisposing syndrome is present, in particular WT1 -associated syndromes and overgrowth syndromes. Constitutional WT1 mutations or ...epigenetic changes on chromosome 11p15 have also been described in Wilms tumour patients without phenotypic abnormalities. Thus, the absence of phenotypic abnormalities does not exclude the presence of a genetic predisposition, suggesting that more Wilms tumour patients may have a constitutional abnormality. Therefore, we investigated the frequency of constitutional aberrations in combination with phenotype. Patients & methods Clinical genetic assessment, as well as molecular analysis of WT1 and locus 11p15 was offered to a single-centre cohort of 109 childhood Wilms tumour patients. Results Twelve patients (11%) had a WT1 aberration and eight patients (8%) had an 11p15 aberration. Of the 12 patients with a WT1 aberration, four had WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations and mental retardation), one had Denys-Drash syndrome, four had genitourinary anomalies without other syndromic features and three had bilateral disease with stromal-predominant histology at young age without congenital anomalies. Of the eight patients with an 11p15 aberration, four had Beckwith–Wiedemann syndrome (BWS), two had minor features of BWS and two had no stigmata of BWS or hemihypertrophy. Conclusion Constitutional WT1 or 11p15 aberrations are frequent in Wilms tumour patients and careful clinical assessment can identify the majority of these patients. Therefore, we would recommend offering clinical genetic counselling to all Wilms tumour patients, as well as molecular analysis to patients with clinical signs of a syndrome or with features that may indicate a constitutional WT1 or 11p15 aberration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Kersseboom R, Dubbink HJ, Corver WE, van Tilburg AJP, Poley JW, van Leerdam ME, Atmodimedjo PN, van de Laar IMBH, Collée JM, Dinjens WNM, Morreau H, Wagner A. PTEN in colorectal cancer; a report on ...two Cowden syndrome patients.
Heterozygous germline PTEN mutations cause Cowden syndrome. The risk of colorectal cancer in Cowden patients, however, remains a matter of debate. We describe two patients presenting with colorectal cancer at a young age (28 and 39 years) and dysmorphisms fitting the Cowden spectrum. Heterozygous germline mutations in PTEN were found in both patients. Moreover, analysis of the resected colorectal cancer specimens revealed loss of heterozygosity at the PTEN locus with retention of the mutated alleles, and greatly reduced or absent PTEN expression. Histologically and molecularly, the tumours showed resemblance with sporadic colorectal cancers, although they had prominent fibrotic stroma. Our data indicate that PTEN loss was involved in carcinogenesis in the two patients, supporting that colorectal cancer is part of the Cowden syndrome‐spectrum. This is in line with data on sporadic colorectal cancer, mice studies and emerging epidemiological data on Cowden syndrome. Although the exact role of germline PTEN mutations in the carcinogenesis of colorectal cancer remains unclear, we think that Cowden syndrome should be in the differential diagnosis of colorectal cancer certainly in view of the possible prognostic and therapeutic consequences. Prospective follow‐up and surveillance of PTEN mutation carriers from the age of 25 to 30 years in a study setting should clarify this issue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Expression of the pre-B cell receptor (pre-BCR) leads to activation of the adaptor molecule SLP-65 and the cytoplasmic kinase Btk. Mice deficient for one of these signaling proteins have an ...incomplete block in B cell development at the stage of large cycling pre-BCR+CD43+ pre-B cells. Our recent findings of defective SLP-65 expression in approximately 50% of childhood pre-B acute lymphoblastic leukemias and spontaneous pre-B cell lymphoma development in SLP-65-/- mice demonstrate that SLP-65 acts as a tumor suppressor. To investigate cooperation between Btk and SLP-65, we characterized the pre-B cell compartment in single and double mutant mice, and found that the two proteins have a synergistic role in the developmental progression of large cycling into small resting pre-B cells. We show that Btk/SLP-65 double mutant mice have a dramatically increased pre-B cell tumor incidence ( approximately 75% at 16 wk of age), as compared with SLP-65 single deficient mice (<10%). These findings demonstrate that Btk cooperates with SLP-65 as a tumor suppressor in pre-B cells. Furthermore, transgenic low-level expression of a constitutive active form of Btk, the E41K-Y223F mutant, prevented tumor formation in Btk/SLP-65 double mutant mice, indicating that constitutive active Btk can substitute for SLP-65 as a tumor suppressor.
During B-cell development in the mouse, Bruton tyrosine kinase (Btk) and the adaptor protein SLP-65 (Src homology 2 SH2 domain-containing leukocyte protein of 65 kDa) limit the expansion and promote ...the differentiation of pre-B cells. Btk is thought to mainly function by phosphorylating phospholipase Cγ2, which is brought into close proximity of Btk by SLP-65. However, this model was recently challenged by the identification of a role for Btk as a tumor suppressor in the absence of SLP-65 and by the finding that Btk function is partially independent of its kinase activity. To investigate if enzymatic activity is critical for the tumor suppressor function of Btk, we crossed transgenic mice expressing the kinase-inactive K430R-Btk mutant onto a Btk/SLP-65 double-deficient background. We found that K430R-Btk expression rescued the severe developmental arrest at the pre-B-cell stage in Btk/SLP-65 double-deficient mice. Moreover, K430R-Btk could functionally replace wild-type Btk as a tumor suppressor in SLP-65- mice: at 6 months of age, the observed pre-B-cell lymphoma frequencies were approximately 15% for SLP-65- mice, 44% for Btk/SLP-65-deficient mice, and 14% for K430R-Btk transgenic mice on the Btk/SLP-65-deficient background. Therefore, we conclude that Btk exerts its tumor suppressor function in pre-B cells as an adaptor protein, independent of its catalytic activity. (Blood. 2005;105:259-265)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Signals from the precursor-B cell receptor (pre-BCR) are essential for selection and clonal expansion of pre-B cells that have performed productive immunoglobulin heavy chain V(D)J recombination. In ...the mouse, the downstream signaling molecules SLP-65 and Btk cooperate to limit proliferation and induce differentiation of pre-B cells, thereby acting as tumor suppressors to prevent pre-B cell leukemia. In contrast, recent observations in human BCR-ABL1
+ pre-B lymphoblastic leukemia cells demonstrate that Btk is constitutively phosphorylated and activated by the BCR-ABL1 fusion protein. As a result, activated Btk transmits survival signals that are essential for the transforming activity of oncogenic Abl tyrosine kinase.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Female nonobese diabetic (NOD) mice more frequently develop autoimmune diabetes than NOD males. Orchidectomy of the latter aggravates insulitis and diabetes. Because clear differences in immune ...function have not been observed between prediabetic females and males, before or after castration, we hypothesized that sex-related differences in diabetes incidence are related to target organ-specific actions of sex steroids. Previously, we showed that prediabetic NOD females develop hyperinsulinemia and subsequently mega-islets. Infiltration of the first inflammatory leukocytes is predominantly associated with these mega-islets. Here, we determined the relationship between sex hormones, mega-islet formation, and infiltrating cells in NOD and nonobese diabetic/severe combined immune-deficient (NODscid) mice. Mega-islet formation was reduced in NOD males compared with NOD females, and orchidectomy increased it, indicating a relationship between androgen levels and mega-islet formation. Moreover, enhanced mega-islet formation in castrated NOD males was associated with increased numbers of infiltrating leukocytes. Castrated NODscid males also exhibited increased mega-islet formation and dendritic cell infiltration, indicating that lymphocytes are not required for castration-induced effects. In conclusion, we show that androgens influence pancreatic islets and autoimmune infiltration in NOD and NODscid mice. This suggests that the gender difference in diabetes incidence in NOD mice is related to target organ-specific androgen effects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Variant Creutzfeldt-Jakob disease (vCJD) is a fatal and untreatable neurological disease, in which pathogenic prions (PrPSc) are involved. There is convincing epidemiological and experimental ...evidence that vCJD is a human expression of bovine spongiform encephalopathy (BSE). The risk of transmission of pathogenic prions which cause vCJD to humans is influenced by the species barrier, genetic susceptibility of the host, dose of infection and route of exposure. Transmission of pathogenic prions from bovines to humans is possible through meat products containing nerve and lymphatic tissue, and through medical products derived from bovine material. Human to human transmission is, in principle, also possible via blood and blood-derived products, human organs and tissues for transplantation, and through surgical instruments. Preventive measures to reduce transmission from bovines to humans have been introduced step by step in the Netherlands since 1989. With proper implementation, the current risk of becoming infected by Dutch meat products is small. It is very likely, however, that in the past decade BSE-infected bovines have entered the food chain. The Dutch population has also been exposed to foreign infected meat products. Measures to prevent human to human transmission are currently being improved in the Netherlands. It is expected that cases of vCJD will occur in the Netherlands in the future, but the number cannot be estimated accurately. The presence of PrPSc in both the livestock and in the human population in the Netherlands constitutes a permanent public health threat and is a reason for continued vigilance and active prevention.
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