Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation

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• 作者：Fabian Hauck^a ; ^b ; ^c ; ¹ ; ² ; ^{fabian.hauck@med.uni-muenchen.de} ; Aude Magerus-Chatinet^a ; ^b ; ¹ ; ^{aude.magerus@inserm.fr} ; Stephanie Vicca^d ; ^{stephanie.vicca@nck.aphp.fr} ; Anne Rensing-Ehl^e ; ^{anne.rensing-ehl@uniklinik-freiburg.de} ; Angela Roesen-Wolff^c ; ^{angela.roesen-wolff@uniklinikum-dresden.de} ; Joachim Roesler^c ; ³ ; ^{joachim.roesler@uniklinikum-dresden.de} ; Fré ; dé ; ric Rieux-Laucat^a ; ^b ; ³ ; ^{frederic.rieux-laucat@inserm.fr}
• 关键词：ALPS ; autoimmune lymphoproliferative syndrome ; DN T cell ; double-negative T cell ; ICD ; intracellular domain ; ECD ; extracellular domain ; LOH ; loss of heterozygosity ; MNR ; mutation-negative relative ; MPR ; mutation-positive relative ; sFASL ; soluble FAS ligan
• 刊名：Clinical Immunology
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：147
• 期：1
• 页码：61-68
• 全文大小：521 K

文摘

We describe a family with 12 members carrying a heterozygous germline FAS c.3G > T start codon mutation leading to FAS haploinsufficiency. One patient had autoimmune lymphoproliferative syndrome (ALPS), one had recovered from ALPS, and ten mutation-positive relatives (MPRs) were healthy. FAS-mediated apoptosis and surface expression of FAS in single-positive T cells were lower for MPRs but did not discriminate between them and the ALPS patient. However, double-negative (DN) T cells of the ALPS patient had no FAS expression due to somatic loss of heterozygosity. Our results in this kindred suggest that FAS haploinsufficiency does not cause ALPS-FAS, but that modifying genetic events are crucial for its pathogenesis. FAS surface expression on DN T cells should be assessed routinely and FAS haploinsufficient patients should be followed as its potential for lymphomagenesis is not well defined and a second hit might occur later on.