A female patient with incomplete hemophagocytic lymphohistiocytosis caused by a heterozygous XIAP mutation associated with non-random X-chromosome inactivation skewed towards the wild-type XIAP allele

Journal of Clinical Immunology
Xi YangHirokazu Kanegane

Abstract

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.

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Citations

Mar 21, 2016·Seminars in Cell & Developmental Biology·Marcella VaccaMaurizio D'Esposito
Jul 15, 2016·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Ole Haagen Nielsen, Eric Charles LaCasse
May 17, 2018·British Journal of Haematology·Rebecca A Marsh, Elie Haddad
Jan 12, 2019·Immunological Medicine·Hirokazu Kanegane
Aug 10, 2019·Frontiers in Immunology·Samuel Cern Cher ChiangRebecca A Marsh
Feb 29, 2020·Blood·Scott W Canna, Rebecca A Marsh
Nov 7, 2016·Journal of Clinical Immunology·Shintaro OnoHirokazu Kanegane
Apr 20, 2020·BMC Pediatrics·Jiamei TangZhifeng Liu
Jan 24, 2018·Frontiers in Immunology·Rebecca A Marsh
Oct 18, 2020·Journal of Personalized Medicine·Paula Iber-DíazRosa M Yañez-Vico
Aug 11, 2020·Seminars in Cell & Developmental Biology·Mary Speir, Kate E Lawlor
Jul 6, 2021·Frontiers in Pediatrics·Anne C A MuddeRebecca A Marsh
Jul 12, 2021·The Journal of Allergy and Clinical Immunology. in Practice·Shintaro OnoHirokazu Kanegane

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