Multiple novel alterations in<i>Kit</i>tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder

Molderings, Gerhard J.; Kolck, Ulrich W.; Scheurlen, C; Brüss, Michael; Homann, Jürgen; Kügelgen, Ivar von

doi:10.1080/00365520701245744

Cited by 67 publications

(59 citation statements)

References 44 publications

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“…Up until now, few researchers have considered the possibility that multiple variants of a gene might preexist within diseasesusceptible tissues, but we are beginning to observe this condition in a few cases [Alvarado et al, 2005;Molderings et al, 2007;Sircar et al, 2007]. New sequencing techniques, such as ultradeep pyrosequencing, are able to overcome limitations in current sequencing protocols that effectively only sequence ''majority'' DNA forms, by being able to ''oversequence'' individual genes thousands of times.…”

Section: Discussionmentioning

confidence: 97%

BAK1 gene variation and abdominal aortic aneurysms

et al. 2009

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We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene (BAK1) that codes for an apoptotic-promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism (SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in "minority" forms within specific nondiseased tissues and be selected for, when intra- and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny.

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Section: Discussionmentioning

confidence: 97%

BAK1 gene variation and abdominal aortic aneurysms

et al. 2009

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“…Most genes have a maximum of two copies in an individual; however, multiple variants can sometimes occur in the same tissues. This has been noted when tumor tissue was compared to nontransformed tissue and up to six different variants of the kit tyrosine kinase gene were found in individuals [Molderings et al, 2007]. As not all of these variants were present in equal amounts, this suggested the presence of both majority and minority DNA species.…”

Section: New Dna Sequencingtechnologiesmentioning

confidence: 85%

Large scale DNA sequencing: new challenges emerge-the 2007 Human Genome Variation Society scientific meeting

Oetting

2008

Hum. Mutat.

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The annual scientific meeting of the Human Genome Variation Society (HGVS) was held on 23 October 2007, in San Diego, CA. The major theme of this meeting was "New DNA Sequencing Technologies & Human Genome Variation." A series of speakers provided information on several new technologies that produce DNA sequence data on a scale far beyond what was possible even a few years ago. These new technologies produce up to gigabases of nucleotides on a single run. Already, two individuals have had their entire genome sequenced, resulting in the identification of many novel DNA variants. Several new questions now need to be answered. What impact do these novel variants have on the phenotypes? How are we to associate private variants in a single individual with disease, especially when current association studies require genotyping thousands of individuals? Further work will be required to create methodologies to analyze these variants to determine if they are potentially disease-producing or are phenotypically silent. For the technology to be useful in a medical setting it will be crucial to answer to these questions.

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“…Bei den systemischen Mastzellüberaktivitätsstö-rungen kommt es dagegen zu einer langsamen Akkumulation von nicht maligne entarteten, aber dennoch pathologisch veränderten (mutierten) Mastzellen in den Geweben des Organismus als Folge eines durch deren unkontrolliert erhöhten Aktivitätszu-stand gestörten Proliferations-und Apoptoseverhaltens (Abbildung 1). Dabei stehen die genetischen Subtypen (Abbildung 1) nicht für verschiedene Erkrankungen, sondern sie sind Teile eines Spektrums von mastzellbedingten Dysfunktionen [2,3]. Die vielfältigen Symptome wie Übelkeit, Durchfall, Darmkrämpfe, Ulcus ventriculi, Flush, Pruritus, Kopfschmerzen, Knochenschmerzen, Hepato-und/oder Splenomegalie werden überwiegend durch unkontrolliert freigesetzte Mediatoren aus den in den Organen und Geweben vorhandenen pathologischen Mastzellen und aus durch diese sekundär aktivierten gesunden Mastzellen [4][5][6][7] verursacht.…”

Section: Was Ist Eine Systemische Mastozytose?unclassified

“…Inzwischen jedoch belegen Befunde zum Vorliegen von Mutationen in der Tyrosinkinase Kit in Mastzellen von Patienten mit chronischen unspezifischen gastrointestinalen Beschwerden als Bestandteil eines Mastzellmediatorsyndroms, dass eine systemische MastozyAbbildung 1. Klassifizierung systemischer Mastozytosen unter Berücksichtigung der Mutationen in den Kinasen und Rezeptorproteinen der Mastzellen (modifiziert nach [1,25] tose eine häufige Erkrankung in der täglichen Praxis ist [2,[8][9][10][11]. Seit einiger Zeit wird zudem darüber diskutiert, ob ein systemisches Mastzellüber-aktivitätssyndrom (Abbildung 1) ursächlich mit dem Reizdarmsyndrom, einer der häufigsten Erkrankungen des Verdauungstrakts (Schätzungen reichen von 5 bis 15 Mio.…”

Section: Prävalenz Der Systemischen Mastozytoseunclassified

“…Nach aktuellen Erkenntnissen führen funktionell aktivierende Mutationen in verschiedenen Kinasen, insbesondere in den Tyrosinkinasen Kit und "plateletderived growth factor receptor α", sowie in Rezeptorproteinen zu einer unkontrollierten Daueraktivierung der betroffenen Mastzellen (Abbildung 1) [1,2,11,[15][16][17][18][19] (Nr. 8) ne Beobachtung, [22][23][24]).…”

Section: Pathophysiologie Der Systemischen Mastozytoseunclassified

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Die systemische Mastozytose – Standortbestimmung einer internistischen Erkrankung

et al. 2010

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Systemic mastocytosis comprises disorders characterized by an accumulation of genetically altered mast cells in all organs and tissues due to an increased proliferation rate and reduced apoptosis of those pathologic mast cells. Release of their mediators can effectively influence organ function and can lead to systemic effects without inducing traces in routinely used laboratory parameters or imaging methods. In most cases, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy consisting of a basic medication with antihistamine and mast cell membrane-stabilizing compounds that should be supplemented, if required, by a medication adapted to individual symptoms, can be initiated. Because of the probably high prevalence of the disorder, systemic mastocytosis should be considered as a differential diagnosis in particular in the case of chronic gastrointestinal complaints such as abdominal pain/discomfort possibly associated with diarrhea, at an early stage.

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Multiple novel alterations inKittyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder

Cited by 67 publications

References 44 publications

BAK1 gene variation and abdominal aortic aneurysms

BAK1 gene variation and abdominal aortic aneurysms

Large scale DNA sequencing: new challenges emerge-the 2007 Human Genome Variation Society scientific meeting

Die systemische Mastozytose – Standortbestimmung einer internistischen Erkrankung

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