Constitutional mismatch repair-deficiency and whole-exome sequencing as the means of the rapid detection of the causative MSH6 defect.

BACKGROUND: Cases of children with more than one type of cancer either diagnosed simultaneously or successively, rarely occur in pediatric oncology. A second malignant neoplasm may be caused by mutagenic effects of the treatment of the primary malignancy and/or may point towards an underlying genetic cancer susceptibility syndrome. One example of such a syndrome is constitutional mismatch repair-deficiency, (CMMR-D) which carries an increased risk of various tumors including childhood hematologic malignancies and Lynch syndrome associated tumors. Timely diagnosis of CMMR-D is crucial, since this diagnosis has implications for the entire family. PATIENT: We report the case of a 15-year-old girl who was born to consanguineous parents. At the age of 20 months she was diagnosed with a T-cell non-Hodgkin lymphoma. Treatment was given according to NHL-BFM 95. 12 years later, an invasive adenocarcinoma of the colon was surgically removed which relapsed shortly afterwards. METHODS: Whole-exome sequencing of germline DNA was employed to rapidly detect the underlying mutation in this suspected CMMR-D patient. RESULTS: After a short turnaround time of less than 3 weeks, the diagnosis of CMMR-D could be confirmed by the identification of a homozygous 29-bp deletion in MSH6 (exon 6), which was confirmed by independent methods. CONCLUSIONS: We demonstrate that "bed-side" whole-exome sequencing is both feasible and cost-effective and may be the method of choice to rapidly uncover the genetical basis of (inherited) diseases.

Deoxynivalenol triggers the expression of IL-8-related signaling cascades and decreases protein biosynthesis in primary monocyte-derived cells.

Humans and their immune system are confronted with mold-contaminated food and/or mold-contaminated air in daily life and indoor activities. This results in metabolic stress and unspecific disease symptoms. Other studies provided evidence that exposure to mold is associated with the etiology of allergies. Deoxynivalenol (DON) is of great concern due to its frequent occurrence in toxically relevant concentrations. The exposure to this toxin is a permanent health risk for both humans and farm animals because DON cannot be significantly removed during standard milling and processing procedures. However, the direct effect on immunity or hematology is poorly defined because most investigations could not separate the effect of DON-contaminated feed intake. Due to the widespread distribution of DON after rapid absorption, it is not surprising that DON is known to affect the immune system. The immune system of the organism has one important function, to defend against the invasion of unknown substances/organisms. This study shows for the first time a synergistic effect of both-low physiological DON-doses in combination with low LPS-doses with the focus on the IL-8 expression on protein and RNA level. Both doses were found in vivo. IL-8 together with other anorectic cytokines like IL-1ß can affect the food intake and anorexia. We could also show that a calcium-response is not involved in the increased IL-8 production after acute DON stimulation with high or low concentrations.

Genomic organization and chromosomal localization of the human peroxisomal membrane protein-1-like protein (PXMP1-L) gene encoding a peroxisomal ABC transporter.

The cDNA of the peroxisomal membrane protein-1-like protein (PXMP1-L, synonyms: PMP69, P70R), a novel peroxisomal ATP binding cassette transporter of yet unknown function, has recently been cloned. The best known peroxisomal member of this protein family is the adrenoleukodystrophy protein, defects of which are the underlying cause of X-linked adrenoleukodystrophy (X-ALD). Here we describe the complete exon-intron structure (19 exons and 18 introns covering 16.0 kb) of the human PXMP1-L gene, transcript variants, the localization on chromosome 14q24 by cytogenetic analysis and sequencing of the putative promoter region. PXMP1-L has been proposed to play a role as a modifier in determining the phenotypic variations observed in X-ALD. The data presented will enable sequence analysis of the PXMP1-L gene in X-ALD patients and facilitate the analysis of PXMP1-L function.

The impact of TEL-AML1 (ETV6-RUNX1) expression in precursor B cells and implications for leukaemia using three different genome-wide screening methods.

The reciprocal translocation t(12;21)(p13;q22), the most common structural genomic alteration in B-cell precursor acute lymphoblastic leukaemia in children, results in a chimeric transcription factor TEL-AML1 (ETV6-RUNX1). We identified directly and indirectly regulated target genes utilizing an inducible TEL-AML1 system derived from the murine pro B-cell line BA/F3 and a monoclonal antibody directed against TEL-AML1. By integration of promoter binding identified with chromatin immunoprecipitation (ChIP)-on-chip, gene expression and protein output through microarray technology and stable labelling of amino acids in cell culture, we identified 217 directly and 118 indirectly regulated targets of the TEL-AML1 fusion protein. Directly, but not indirectly, regulated promoters were enriched in AML1-binding sites. The majority of promoter regions were specific for the fusion protein and not bound by native AML1 or TEL. Comparison with gene expression profiles from TEL-AML1-positive patients identified 56 concordantly misregulated genes with negative effects on proliferation and cellular transport mechanisms and positive effects on cellular migration, and stress responses including immunological responses. In summary, this work for the first time gives a comprehensive insight into how TEL-AML1 expression may directly and indirectly contribute to alter cells to become prone for leukemic transformation.

[The impacted intramedullary nail. Re-discovery of an old problem with a new nail]. / Der festgelaufene Marknagel. Die Wiederentdeckung eines alten Problems an einem neuen Nagel.

Impaction of an intramedullary nail during extraction is an unpredictable and delicate situation. Its problematic nature is unfolded on a report of two cases, one with a Küntscher nail and one with a modern solid titanium nail. This event is caused by ingrowth of new bone formation into the slot or the dorsal flute respectively. The new bone formation is a mechanical barrier which effectively forces the distal part of the nail to jam against the cortex. Both, the slot of the unlocked reamed clover leaf nail and the wider dorsal flute of the solid titanium nail, realize certain therapeutic concepts. Their factual benefit within the concept of interlocking nailing is doubtful.

[Existence of a retinaculum musculorum extensorum immum in man]. / Uber die Existenz eines Retinaculum musculorum extensorum imum beim Menschen.

The considerable variability of the Mm. extensor hallucis longus et brevis and the medial portion of the M. extensor digitorum brevis reflects the higher strain acting on the medial part of the forefoot. These functional conditions result probably not only in the increased development of the muscles mentioned above but also in the formation of a Retinaculum musculorum extensorum imum, which does, in fact, occur in 64.2% of extremities examined. 2 major forms of this retinaculum can be differentiated: A Retinaculum musculorum extensorum imum fibrosum (52.3%) and musculofibrosum (11.9%). The fibrous form again occurs in 2 varieties, namely a complete (47%) and an incomplete (5.3%) one.

[Vascular problems in patients with transplants from the interdisciplinary viewpoint]. / Vaskuläre Probleme beim Transplantierten aus interdisziplinärer Sicht.

From 1979 to 12/1990 795 organ transplants have been performed at our hospital (kidney n:737, liver n:23, heart n:35). Our data reveal vascular problems in 10 percent of the transplanted patients - not concerning the vascular anastomosis. The therapeutic approach should be determined interdisciplinary. Due to the low complication rate of operative or interventionel procedures in this patients, even relative indications--to improve "quality of live"--can be accepted.

Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p.

Four ABC half transporters (ALDP, ALDRP, PMP70, and PMP69) have been identified in the mammalian peroxisomal membrane but no function has been unambiguously assigned to any of them. To date X-linked adrenoleukodystrophy (X-ALD) is the only human disease known to result from a defect of one of these ABC transporters, ALDP. Using the yeast two-hybrid system and in vitro GST pull-down assays, we identified the peroxin PEX19p as a novel interactor of ALDP, ALDRP, and PMP70. The cytosolic farnesylated protein PEX19p was previously shown to be involved in an early step of the peroxisomal biogenesis. The PEX19p interaction occurs in an internal N-terminal region of ALDP which we verified to be important for proper peroxisomal targeting of this protein. Farnesylated wild-type PEX19p and a farnesylation-deficient mutant PEX19p did not differ in their ability to bind to ALDP. Our data provide evidence that PEX19p is a cytosolic acceptor protein for the peroxisomal ABC transporters ALDP, PMP70, and ALDRP and might be involved in the intracellular sorting and trafficking of these proteins to the peroxisomal membrane.