X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

Abstract

Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.

First Case of X-Linked Moesin Deficiency Identified After Newborn Screening for SCID

“…Our case suggests that, in the presence of a male infant with a positive SCID newborn screening and fluctuating neutropenia and monocytopenia, diagnosis of X-MAID should be considered. Despite an immunological phenotype that matches our patients, the infectious history of the patients previously reported with the p.R171W mutation was more severe, even when adjusting for age, and included susceptibility to bacterial and VZV infections [4]. It is known that, in SCID patients, early diagnosis allows initiation of appropriate prophylactic measures that reduce the incidence and severity of infections, improving morbidity and outcome of hematopoietic stem cell transplantation (HSCT) [1].…”

“…S1b). The p.R171W mutation has been previously reported in six patients with X-MAID and is associated with reduced protein expression [4]. Interestingly, the patient’s maternal grandmother had a brother who died at 19 years of age after a history of recurrent infections.…”

“…This immunodeficiency is caused by genetic defects of the moesin ( MSN ) gene [4]. The seven patients currently reported in the literature did not undergo newborn screening.…”

“…Subjects with X-MAID have a normal-sized thymus but few naïve T cells. This has led to hypothesize that the T cell lymphopenia could be due to impaired cellular egress from the thymus rather than a defect of T cell differentiation [4]. However, this hypothesis is challenged by the observation that the vast majority of CD4 + cells from our patients had a naïve phenotype and an increase in the percentage of CD8 + cells with an “exhaustion” phenotype (CD45RA + CCR7 − ) was only observed during follow-up (Table 1).…”

Studying human immunodeficiencies in humans: advances in fundamental concepts and therapeutic interventions

“…Examples of these discoveries are those caused by autosomal or hemizygous recessive mutations in BCL10 11 , CD70 12, 13 , CTPS1 14 , DOCK2 15 , MSN 16 , NIK 17 , RASGRP1 18 , RLTPR 19 , and TRFC 20 ; haploinsufficient mutations in IKAROS 21 or NFKB1 22 ; as well as a heterozygous dominant negative mutation in BCL11B 8 . Other examples include humoral immunodeficiency accompanying multi-organ autoimmunity caused by haploinsufficient mutations in CTLA4 23, 24 or gain-of-function mutations in STAT3 25 ; as well as neutrophil dysfunction caused by autosomal recessive mutations in JAGN1 26 or WDR1 27 .…”