MSN – Combined Immunodeficiency Due to Moesin Deficiency

Combined immunodeficiency due to moesin deficiency (X-MAID; MONDO:0010514) is an X-linked recessive disorder characterized by profound lymphopenia, hypogammaglobulinemia, recurrent bacterial and viral infections, and mucocutaneous ulcerations. Patients often present in early childhood with severe lymphocyte defects and impaired adaptive immunity. Initial reports described seven male patients from five unrelated families with hemizygous MSN mutations, demonstrating segregation with disease in all kindreds (PMID:27405666). Subsequent case reports expanded the cohort with one proband diagnosed by WES (PMID:29556235), one boy presenting with colitis-like symptoms (PMID:35754805), two affected siblings with autoimmune thyroiditis and antiphospholipid syndrome (PMID:36119109), and a Chinese patient with EBV-driven lymphoma and dermatomyositis-like features (PMID:38922539), totaling 12 hemizygous probands.

All pathogenic variants reported are hemizygous in males and include both loss-of-function and deleterious missense changes. A recurrent missense variant, c.511C>T (p.Arg171Trp), has been observed in multiple families, while truncating alleles such as c.504G>A (p.Trp168Ter) have also been reported. Segregation analysis confirms X-linked recessive inheritance with full penetrance in hemizygotes and carrier status in heterozygous females.

Functional studies demonstrate that mutant moesin leads to deficient T-cell proliferation, poor chemokine receptor expression, and impaired migration. In vitro reconstitution of wild-type MSN restores T-cell proliferation and adhesion in patient-derived lymphocytes, confirming a loss-of-function mechanism (PMID:27405666; PMID:29556235). Reduced moesin protein and mRNA levels have been documented by Western blot and qPCR, correlating with clinical severity.

The phenotypic spectrum has broadened beyond classic immunodeficiency to include inflammatory bowel disease-like colitis, autoimmune endocrinopathies, antiphospholipid syndrome, and EBV-associated malignancy. These findings underscore the need for immunological and genetic evaluation in male patients with early-onset multisystem autoimmune and infectious presentations.

Integration of genetic segregation, multiple independent case reports totaling 12 probands, and concordant functional rescue studies supports a Strong ClinGen classification for the MSN–combined immunodeficiency association. Genetic testing for MSN variants should be considered in male patients with severe lymphopenia and mucocutaneous manifestations. Key take-home: X-linked moesin deficiency is a clinically actionable immunodeficiency with defined genetic and functional hallmarks.

References

• The Journal of Allergy and Clinical Immunology • 2016 • X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene. PMID:27405666
• Frontiers in Immunology • 2018 • Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case. PMID:29556235
• Frontiers in Genetics • 2022 • A Novel Variant of X-Linked Moesin Gene in a Boy With Inflammatory Bowel Disease Like Disease-A Case Report. PMID:35754805
• Frontiers in Immunology • 2022 • Hemizygous nonsense variant in the moesin gene (MSN) leads to a new autoimmune phenotype of Immunodeficiency 50. PMID:36119109
• Journal of Clinical Immunology • 2024 • Novel Mutation in the Moesin (MSN) Gene Leads to Immunodeficiency with Epstein-Barr Virus (EBV) Infection and Dermatomyositis-Like Symptoms. PMID:38922539

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