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Zeitschrift für Rheumatologie

, Volume 76, Issue 4, pp 303–312 | Cite as

Rolle der Genetik beim familiären Mittelmeerfieber

Leitthema

Zusammenfassung

Das familiäre Mittelmeerfieber (FMF) wird durch Mutationen im Mediterranean Fever-Gen (MEFV) verursacht, die eine Überaktivierung des Pyrin-Inflammasoms und damit eine unverhältnismäßige proinflammatorische Reaktion auslösen. Häufig finden sich bei FMF-Patienten 2 pathogene Mutationen, die beide Allele betreffen. Zusätzlich tritt ein klinisch diagnostiziertes FMF bei Patienten mit kombiniert heterozygotem Mutationsstatus und Vorliegen von Mutationen mit geringerer Penetranz, bei einfach oder komplex heterozygoten Patienten oder in Einzelfällen auch ohne Nachweis von Mutationen auf. Zudem können sich bei heterozygoten Anlageträgern, die nicht an einem klinischen FMF leiden, andere inflammatorische Phänomene zeigen wie eine anhaltende subklinische Inflammation, eine Assoziation zu anderen entzündlichen Erkrankungen oder weitere unspezifische Krankheitssymptome. Somit folgt das FMF nicht einem klassischen autosomal-rezessiven Erbgang, vielmehr liegt eine Gendosis-Wirkungsbeziehung vor. Die phänotypische Präsentation wird darüber hinaus auch von weiteren Einflüsse, wie z. B. genetischen Varianten, die nur teilweise bekannt sind, und Umweltfaktoren mit geprägt. Die vorliegende Arbeit beschreibt das weite Spektrum der Auswirkung von MEFV-Mutationen auf den Phänotypen der Merkmalsträger und fasst Arbeiten zusammen, die die Gendosis-Wirkungsbeziehung der MEFV-Mutationen analysieren. Im Weiteren wird der Stellenwert der molekulargenetischen Diagnostik in Bezug auf die Diagnosestellung eines FMF sowie auf ein individualisiertes Management diskutiert.

Schlüsselwörter

Autoinflammation Inflammasom Umweltfaktoren Phänotyp Mutationen 

Role of genetics in familial Mediterranean fever

Abstract

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with a subsequent disproportional proinflammatory reaction. Classically, in FMF patients two pathogenic mutations affecting both alleles are found in the molecular genetic analysis; however, it is well known that the phenotype can also be caused either by mutations with lower penetrance or unknown significance. Furthermore, in a significant number of patients only one or even no MEFV mutations can be detected. Heterozygous mutation carriers who do not suffer from classical FMF, can also present with other signs of inflammation, e. g. subclinical increased inflammation markers, associated inflammatory diseases or unclassified symptoms. Thus, FMF does not follow a classical autosomal recessive inheritance and a variable gene dose effect has to be considered, which is furthermore modulated by other mostly unknown genetic variants and environmental factors. This article summarizes the broad spectrum of clinical presentations associated with MEFV mutations and analyzes the effect of the gene dose on the phenotypical expression. Furthermore, the impact of the molecular genetic analysis on the diagnostics of a patient and on the individualized management of the disease is discussed.

Keywords

Autoinflammation Inflammasome Environmental factors Phenotype Mutations 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

T. Kallinich, B. Orak und H. Wittkowski geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Klinik für Pädiatrie m.S. Pneumologie und ImmunologieCharité Universitätsmedizin BerlinBerlinDeutschland
  2. 2.Interdisziplinäres Sozialpädiatrisches ZentrumCharité Universitätsmedizin BerlinBerlinDeutschland
  3. 3.Klinik für Pädiatrische Rheumatologie und ImmunologieUniversitätsklinikum MünsterMünsterDeutschland

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