OCRL – Dent disease type 2

OCRL encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase localized to endosomes and the Golgi, with key roles in receptor-mediated endocytosis in renal proximal tubule cells. Pathogenic variants in OCRL cause X-linked Dent disease type 2 (MONDO:0010359), characterized by low-molecular-weight proteinuria, hypercalciuria, short stature and mild intellectual disability (PMID:28018608; PMID:35098431).

Inheritance is X-linked recessive, with at least eight unrelated male probands harboring OCRL loss-of-function variants: six boys with novel truncating or missense mutations in exon 7–23 (PMID:19390221), plus two singleton cases with large exon 3 deletion and missense change p.Ala51Val (PMID:28018608; PMID:35098431). Segregation follows classic X-linked transmission with affected males and carrier females.

The variant spectrum in Dent 2 includes nonsense, frameshift, splice-site and missense alleles. A recurrent nonsense mutation, c.943C>T (p.Gln315Ter), has been observed in two unrelated families and segregates with disease status (PMID:19390221). Other alleles include multi-exon deletions and splice-disrupting intronic changes.

Functional studies demonstrate that OCRL loss of function leads to ectopic accumulation of PtdIns(4,5)P₂ in endolysosomes, hyperpolymerization of F-actin and defective recycling of the multiligand receptor LRP2 (megalin), resulting in low molecular weight proteinuria and hypercalciuria. In a humanized Ocrl^Y/– mouse model, proximal tubule cells replicate the Dent 2 renal phenotype with massive urinary protein loss and impaired endocytic uptake (PMID:30590522).

In vitro splicing assays and patient RNA analyses confirm that intronic variants such as c.723-2A>C cause exon skipping and in-frame deletions that abolish OCRL catalytic function, consolidating LOF as the primary mechanism in Dent 2 pathogenesis.

Taken together, genetic and experimental data establish a definitive association between OCRL and Dent disease type 2, supporting molecular diagnosis, genetic counseling, and future therapeutic development that target endosomal PtdIns(4,5)P₂ homeostasis.

References

• Nephron Physiology • 2009 • OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. PMID:19390221
• CEN Case Reports • 2022 • A case of Dent disease type 2 with large deletion of OCRL diagnosed after close examination of a school urinary test. PMID:35098431
• Human Genome Variation • 2016 • Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation. PMID:28018608
• Human Molecular Genetics • 2019 • OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease. PMID:30590522

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