PIK3R1 – SHORT syndrome

SHORT syndrome (MONDO:0010026) is an autosomal dominant multisystem disorder characterized by short stature, joint hyperextensibility, ocular depression, Rieger anomaly, delayed tooth eruption, and partial lipodystrophy. Clinical diagnosis is often prompt based on the characteristic facial gestalt (triangular face, prominent forehead, small chin) and metabolic features including insulin resistance. PIK3R1 encodes the p85α regulatory subunit of class IA phosphoinositide 3-kinase (PI3K), a key mediator of insulin and growth factor signaling. Heterozygous loss-of-function mutations in PIK3R1 have been established as the primary molecular cause of SHORT syndrome. This summary reviews genetic and functional data supporting the PIK3R1–SHORT syndrome association to guide clinical decision-making and research.

Genetic evidence for PIK3R1 in SHORT syndrome is robust. Whole-exome sequencing in an initial family trio identified a de novo frameshift mutation c.1906_1907insC (p.Lys575GlufsTer5) in PIK3R1, followed by the identification of four additional heterozygous mutations in three unrelated probands and two affected family members ([PMID:23810382]). Subsequent sequencing in nine individuals from eight families revealed both truncating and missense variants clustering in the inter-SH2 domain ([PMID:23810378]). The recurrent hotspot variant c.1945C>T (p.Arg649Trp) has been observed de novo or segregating in up to eight families, confirming allelic heterogeneity and recurrence ([PMID:23980586]).

Inheritance is strictly autosomal dominant, with most pathogenic variants arising de novo. Family studies have documented transmission from an affected parent to offspring in at least three pedigrees, and multiple sporadic cases confirm de novo mutational events. The PIK3R1 variant spectrum includes frameshift, nonsense, splice-site, and missense mutations. The most commonly reported mutation, c.1945C>T (p.Arg649Trp), accounts for approximately 40% of alleles. Other recurrent truncating variants such as c.1906_1907insC (p.Lys575GlufsTer5) have been described in independent lineages. Allele-specific founder effects have not been reported, and carrier frequency remains exceedingly low.

Functional studies converge on a loss-of-function mechanism leading to downregulation of the PI3K-AKT-mTOR pathway. Lymphoblastoid cells derived from patients harboring truncating PIK3R1 mutations exhibit markedly reduced phosphorylation of the downstream S6 target, indicating impaired pathway activation ([PMID:23810382]). A knockin mouse model heterozygous for the orthologous Arg649Trp variant recapitulates human features including reduced body size, lipodystrophy, and systemic insulin resistance, further validating pathogenesis in vivo ([PMID:26974159]). Rescue experiments or overexpression studies in cell lines confirm that mutant p85α fails to support normal PI3K signaling under insulin and growth factor stimulation.

Conflicting evidence arises from overlap with activated PI3Kδ syndrome type 2 (APDS2), where certain splice-site variants in PIK3R1 confer gain-of-function in leukocytes leading to immunodeficiency, lymphadenopathy, and Hyper-IgM syndrome. Notably, the same c.1425+1G>C splice variant has been associated with both APDS2 and mild features of SHORT syndrome with incomplete penetrance, highlighting domain-specific functional consequences ([PMID:35789397]). This underscores the need for comprehensive phenotyping and consideration of immune evaluation in patients presenting with SHORT syndrome-like features.

In summary, the association between PIK3R1 and SHORT syndrome is supported by strong genetic evidence from at least 14 unrelated probands, multiple de novo events, familial segregation, and consistent functional concordance with PI3K pathway hypofunction. Functional models in patient cells and mouse knockin recapitulate key clinical features, solidifying the haploinsufficiency mechanism. Genetic testing for PIK3R1 variants is clinically actionable for diagnosis, genetic counseling, and potential metabolic management. Key Take-home: PIK3R1 loss-of-function variants cause SHORT syndrome via impaired PI3K-AKT-mTOR signaling, guiding precision diagnosis and future therapeutic research.

References

• American Journal of Human Genetics • 2013 • Mutations in PIK3R1 cause SHORT syndrome PMID:23810382
• American Journal of Human Genetics • 2013 • PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy PMID:23810378
• Clinical Genetics • 2014 • PIK3R1 mutations in SHORT syndrome PMID:23980586
• 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

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