Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Adenosine deaminase 2 (ADA2) deficiency (DADA2) is an inherited immune disorder.
• It presents with vasculopathy and blood-related immune issues.
• Diagnosis typically requires low ADA2 activity and two harmful ADA2 gene variants.

Purpose of the Study:

• To investigate patients with DADA2-like symptoms but only one identified ADA2 gene variant.
• To determine the impact of specific ADA2 missense variants on protein function.

Main Methods:

• Phenotypic analysis of ten patients from seven families.
• In vitro assessment of ADA2 protein expression, secretion, and enzymatic activity for identified variants.

Main Results:

• Ten patients with DADA2-like phenotypes carried a single pathogenic ADA2 variant.
• Several missense variants (p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, p.Y453C) showed dominant negative effects.
• These effects impacted ADA2 enzymatic activity, dimerization, and/or secretion.

Conclusions:

• Heterozygous individuals with dominant negative ADA2 missense variants are at risk for DADA2.
• This expands the understanding of DADA2 inheritance and diagnosis.