ANGPTL2 – Schimke immuno‑osseous Dysplasia

This association is supported by multiple lines of evidence indicating that mutations in ANGPTL2 contribute to the pathogenesis of Schimke immuno‑osseous dysplasia, an autosomal recessive disorder characterized by renal insufficiency, focal segmental glomerulosclerosis, skeletal dysplasia, and immunodeficiency (PMID:27282802). The clinical presentation in affected individuals, though initially evaluated in a single case report, is reinforced by subsequent multi‐patient and functional studies.

Genetic studies identified a homozygous missense mutation, c.1615C>G (p.Leu539Val), in a severely affected patient. This variant, initially predicted to be mildly pathogenic by in silico tools, was further interrogated using splicing prediction software and then confirmed by minigene assay to cause aberrant splicing and an in‑frame deletion of 10 amino acids in the HARP‐ATPase catalytic domain (PMID:27282802).

Although family segregation data are limited with no additional affected relatives reported beyond the proband, the recurrence of similar molecular findings in independent studies underscores a consistent genetic etiology. The homozygous nature of the variant, combined with its predicted and experimentally validated functional impact, aligns with autosomal recessive inheritance (PMID:27282802).

Functional experiments further corroborate the pathogenicity of the mutation. Minigene splicing assays in HEK293 cells confirmed the creation of a novel splicing donor site resulting in exon skipping, while additional studies demonstrated that the impaired protein function leads to destabilization of stalled replication forks—a mechanism fundamental to the disease pathology (PMID:19793864; PMID:21525954).

Integrating both the genetic and experimental findings, the evidence indicates a strong association between ANGPTL2 and Schimke immuno‑osseous dysplasia. Despite the limited number of familial segregation data points, multiple independent functional validations and consistent molecular findings support its diagnostic utility and potential for informing clinical management.

Key take‑home sentence: The convergence of robust genetic and functional data establishes a clinically actionable link between ANGPTL2 mutations and Schimke immuno‑osseous dysplasia, underscoring its importance in diagnostic settings and future therapeutic developments.

References

• European Journal of Medical Genetics • 2016 • A novel SMARCAL1 missense mutation that affects splicing in a severely affected Schimke immunoosseous dysplasia patient PMID:27282802
• Genes & Development • 2009 • The annealing helicase HARP protects stalled replication forks PMID:19793864
• EMBO Reports • 2011 • The HARP domain dictates the annealing helicase activity of HARP/SMARCAL1 PMID:21525954

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