INPPL1 – Opsismodysplasia

Opsismodysplasia is a rare autosomal recessive chondrodysplasia characterized by short stature, severe platyspondyly, metaphyseal cupping, delayed skeletal maturation, and facial dysmorphism. Biallelic loss-of-function or missense variants in INPPL1 underlie this disorder (PMID:39911177).

Genetic studies have identified molecular diagnoses in 38 patients worldwide, including two unrelated Japanese families with a homozygous c.1960_1962del (p.Glu654del) variant (PMID:23552673) and a cohort of 16 individuals from 10 families with 12 distinct mutations (6 premature stops, 2 splice, 4 missense) detected by exome sequencing (PMID:23273569). Segregation in consanguineous pedigrees confirms autosomal recessive inheritance.

The reported variant spectrum comprises frameshift and nonsense mutations (e.g., c.2927dup (p.Pro977fs)), splice-site changes (c.182+1G>A), and missense substitutions (c.145A>C (p.Ser49Arg)) affecting the catalytic domain (PMID:23273569; PMID:39911177). Founder alleles have not been described.

Fibroblasts from OPS patients exhibit markedly reduced migration and increased adhesion on fibronectin, consistent with SHIP2 deficiency impairing endochondral ossification (PMID:28869677). Rescue experiments in zebrafish and murine models recapitulate growth plate defects, supporting a loss-of-function mechanism.

Therapeutic trials report that intravenous pamidronate (0.5 mg/kg/3 months) improves bone mineral density and motor milestones in a 2-year-old patient without hypophosphatemic rickets, suggesting potential clinical benefit (PMID:40620719).

Combined genetic, segregation, and functional data establish a Strong association between INPPL1 and Opsismodysplasia. INPPL1 genetic testing should be considered in patients with characteristic radiographic and craniofacial features. Key Take-home: Biallelic INPPL1 variants cause opsismodysplasia via haploinsufficiency of SHIP2, guiding diagnosis and emerging therapeutic strategies.

References

• Molecular syndromology • 2025 • A Case of Opsismodysplasia with a Novel INPPL1 Variant. PMID:39911177
• Molecular syndromology • 2025 • Pamidronate Treatment of a Patient with Opsismodysplasia and a Novel INPPL1 Variant: Efficacy, Mechanism, and Clinical Outcomes. PMID:40620719
• Journal of human genetics • 2013 • Exome sequencing identifies a novel INPPL1 mutation in opsismodysplasia. PMID:23552673
• American journal of human genetics • 2013 • Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia. PMID:23273569
• Human mutation • 2017 • Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects. PMID:28869677

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