OCRL – Dent Disease (Dent-2)

Dent disease 2 is an X-linked recessive renal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, and progressive renal failure. It arises from loss-of-function mutations in OCRL, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase, and represents a milder allelic variant of Lowe syndrome without congenital cataracts or metabolic acidosis.

Genetic studies in CLCN5-negative families identified pathogenic OCRL variants in 5 of 13 pedigrees with a Dent phenotype, confirming OCRL as a second Dent disease gene and establishing genetic heterogeneity (5 families) (PMID:15627218). Variant classes include truncating, splice-site, and missense changes, such as c.952C>T (p.Arg318Cys), segregating in affected males.

Supplementary case reports expand the spectrum with splice-site alterations (e.g., c.388+3A>G) presenting with atypical Dent-2 phenotypes and mild extrarenal features (PMID:23047739).

Functional assays in patient fibroblasts demonstrate markedly reduced PIP2 5-phosphatase activity and absence of OCRL protein on western blot, accompanied by impaired endosomal trafficking, supporting a loss-of-function mechanism (PMID:15627218).

OCRL mutations also underlie Lowe syndrome; however, Dent-2 variants typically cluster outside critical catalytic residues and preserve residual enzyme activity, correlating mutation location with phenotype distinction (PMID:19390221).

Integrating genetic and experimental data yields a Strong gene-disease association. OCRL testing is recommended in CLCN5-negative patients with a Dent phenotype to enable accurate diagnosis, prognosis, and familial counseling.

Key Take-home: Genetic screening of OCRL guides the diagnosis of Dent disease 2 and informs clinical management.

References

• American journal of human genetics • 2005 • Dent Disease with mutations in OCRL1 PMID:15627218
• Nephron. Physiology • 2009 • OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability PMID:19390221
• World journal of pediatrics • 2011 • OCRL1 mutation in a boy with Dent disease, mild mental retardation, but without cataracts PMID:21822997
• European journal of human genetics • 2013 • An atypical Dent's disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes PMID:23047739

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