Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1)

Abstract

Leukocyte adhesion deficiency type-1 (LAD-1) is an autosomal recessive immunodeficiency caused by mutations in the ␤2 integrin, CD18, that impair CD11/CD18 heterodimer surface expression and/or function. Absence of functional CD11/ CD18 integrins on leukocytes, particularly neutrophils, leads to their incapacity to adhere to the endothelium and migrate to sites of infection. We studied 3 LAD-1 patients with markedly diminished neutrophil CD18 expression, each of whom had a small population of lymphocytes with normal CD18 expression (CD18 ؉ ). These CD18 ؉ lymphocytes were predominantly cytotoxic T cells, with a memory/effector phenotype. Microsatellite analyses proved patient origin of these cells. Sequencing of T-cell subsets showed that in each patient one CD18 allele had undergone further mutation. Interestingly, all 3 patients were young adults with inflammatory bowel disease. Somatic reversions of inherited mutations in primary T-cell immunodeficiencies are typically associated with milder clinical phenotypes. We hypothesize that these somatic revertant CD18 ؉ cytotoxic T lymphocytes (CTLs) may have altered immune regulation. The discovery of 3 cases of reversion mutations in LAD-1 at one center suggests that this may be a relatively common event in this rare disease. IntroductionSomatic mosaicism due to site-specific reversions of inherited mutations to wild type has received much attention in the last decade. 1-7 Some of these reversions have expanded in the host, leading to speculation about possible survival advantages conferred on the cell population carrying the reverted normal sequence. The events leading to somatic mosaicism as a result of reversion of inherited mutations to normal are in principal different from germ-line mosaicism or somatic mosaicism due to de novo mutation. 7 Pathologic mutations that have reverted to wild type have been considered paradigms of endogenous somatic gene therapy. 5,[8][9][10] Unusual phenotypes have alerted investigators to this sort of mosaicism, such as a milder-thanexpected disease course, progressive improvement of disease, or detection of phenotypically normal and abnormal cells. Several different mechanisms have been suggested to be responsible for these events: intragenic recombination, mitotic gene conversion, second-site mutations, DNA slippage, and site-specific reversion to normal. The "back mutation" or "repair" process is most likely random and may reflect an increased mutation rate in certain disorders or mutational hot spots. 7,8,11 Somatic reversions have been described in epidermolysis bullosa, tyrosinaemia type I, Duchenne muscular dystrophy, Lesch-Nyhan disease, Charcot-Marie-Tooth disease type 1A, and Fanconi anemia. [11][12][13][14] Among the primary immunodeficiencies, reversions in adenosine deaminase deficiency, X-linked severe combined immunodeficiency, and Wiskott-Aldrich syndrome confer selective growth advantage on the corrected cells. 1,2,4,5,9,10 Leukocyte adhesion deficiency type-1 (LAD-1) is an autosomal recessive disease caused by ...

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

“…Mosaicism due to somatic gene reversion has been observed in the immune system as well as in various other disease entities. [1][2][3][4][5][6]17,[35][36][37] Here we report a novel X-(S)CID family with a unique mutation in the extracellular part of CD132.…”

“…Most spontaneous reversions have been found to occur in severe skin disease and hematologic or immunological diseases. [2][3][4][5][6] The growth advantage of revertant cells has been the central dogma for the success of gene therapy in severe combined immunodeficiency (SCID). 7,8 SCID is a collection of various gene defects that result in the absence of T lymphocytes with or without the involvement of B cells and/or NK cells.…”

“…Reversed mutations have also been found in patients with Wiskott-Aldrich syndrome [15][16][17] and other primary T-cell immunodeficiencies such as those caused by mutations in CD3zeta, RAG-1, LAD and NEMO. 5,[18][19][20][21] The most common type of SCID in humans shows X-linked inheritance and is caused by mutations in the IL2RG gene. 22,23 This gene encodes an essential subunit, the common γ-chain (γ c , CD132), of a cytokine receptor subfamily that is essential for lymphocyte development, T-cell homeostasis, and peripheral immune responses.…”

Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency

“…Genetic reversions have recently been reported in several different primary immunodeficiencies. 9,[30][31][32][33][34][35][36] A common theme is the selective survival advantage of the revertant immune cells over mutant cells, which has been amply discussed in terms of its implications for gene therapy. 31 Our data confirm the enormous developmental potential of a single T-cell precursor in humans.…”

Detection of leukocyte adhesion deficiency type 1 in an infant by high-throughput targeted exome sequencing

“…Even though flow cytometer (FCM) [4] provides a tool for its diagnosis, it is not available in many hospitals. Genetic analysis is an effective alternative for diagnosis [16] 8 [13] 9 [13] 10 [13] 11 [13] 12 [13] 13 [17] 14 [11] 15 [13] 16 [18] 17 [19] 18 [20] 19 [21] 20 [22] 21 [22] 22 [23] 23 [24] 24 [25] 25 [26] 26 [27] 27 [13] 28 [11] 29 [27] 30 [27] F [13] 32 [28] 33 [25] 34 [29] 35 [27] 36 [30] 37 [31] 38 [13] 39 [32] 40 [33] 41 [29] 42 [13] 43 [34] 44 [22] 45 [11] 46 [13] 47 [13] 48 [35] 49 [26] 50 [22] 51 [13] 52 [36] 53 [15] 54 [29] 55 …”