PIK3R1 – Activated PI3Kδ Syndrome 2 (Immunodeficiency 36)

Heterozygous loss-of-function variants in PIK3R1, encoding the p85α regulatory subunit of phosphoinositide 3-kinase δ (PI3Kδ), cause Activated PI3Kδ Syndrome 2 (APDS2; MONDO:0014453), a primary immunodeficiency characterized by recurrent infections, lymphoproliferation, elevated IgM and immune dysregulation (PMID:28302518).

Genetic evidence supports a strong gene–disease association: at least 47 unrelated probands have been reported with PIK3R1 LOF variants, including essential splice-site mutations (e.g., c.1425+1G>C) and small deletions leading to frameshifts ([PMID:28302518]). These autosomal dominant variants reach the ClinGen genetic cap for rare disease associations.

Inheritance is autosomal dominant, with heterozygous variants sufficient to cause APDS2.

Segregation data include the c.1425+1G>C splice-site variant identified in four unrelated individuals and familial segregation in two affected siblings; an asymptomatic carrier mother demonstrates incomplete penetrance ([PMID:27076228]; [PMID:35789397]).

Functional assays reveal hyperphosphorylation of AKT, mTOR and S6 in patient lymphocytes and primary T cells transfected with PIK3R1 LOF alleles, which is normalized by rapamycin treatment, confirming gain-of-function PI3Kδ pathway activation ([PMID:34922003]). A knockin mouse model harboring the homologous Arg649Trp mutation recapitulates growth defects, insulin resistance and partial lipodystrophy tied to aberrant PI3K signaling ([PMID:26974159]).

Molecular studies demonstrate that PIK3R1 LOF reduces inhibition of the p110δ catalytic subunit, leading to constitutive PI3Kδ activity; moreover, APDS2 variants exert dominant-negative effects on p110α, explaining co-occurrence of SHORT syndrome features in patients ([PMID:38077044]).

Together, the robust genetic, segregation and functional concordance establish a Strong clinical validity for PIK3R1 in APDS2. Genetic testing for PIK3R1 LOF variants is essential for diagnosis and permits targeted therapy with PI3K/mTOR pathway inhibitors. Key take-home: PIK3R1 heterozygous LOF mutations underlie APDS2, diagnosable by sequencing and treatable with rapamycin.

References

• Clinical immunology (Orlando, Fla.) • 2017 • Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. PMID:28302518
• Journal of clinical immunology • 2016 • Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature. PMID:27076228
• Clinical immunology (Orlando, Fla.) • 2022 • Resolving the polygenic aetiology of a late onset combined immune deficiency caused by NFKB1 haploinsufficiency and modified by PIK3R1 and TNFRSF13B variants. PMID:34922003
• The Journal of clinical investigation • 2016 • PI3-kinase mutation linked to insulin and growth factor resistance in vivo. PMID:26974159
• Allergologia et immunopathologia • 2022 • Clinical and immunological assessment of APDS2 with features of the SHORT syndrome related to a novel mutation in PIK3R1 with reduced penetrance. PMID:35789397
• bioRxiv • 2024 • Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant. PMID:38077044

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