OCRL – Oculocerebrorenal Syndrome of Lowe

Oculocerebrorenal syndrome of Lowe (Lowe syndrome) is an X-linked recessive multisystem disorder caused by loss-of-function variants in the OCRL gene (HGNC:8108), manifesting with the clinical triad of congenital bilateral cataracts, intellectual disability, and proximal renal tubular dysfunction (PMID:9199559). The disease is cataloged as Oculocerebrorenal syndrome (MONDO:0010645).

Genetic evidence for the OCRL–Lowe syndrome association is robust, with over 200 distinct hemizygous variants—including nonsense, frameshift, splice-site, and missense changes—identified in more than 150 unrelated families worldwide over 25 years, all demonstrating X-linked segregation and complete penetrance in hemizygous males (PMID:10923037; PMID:27708066). In one seminal study, 106 affected boys from 88 families with OCRL variants exhibited consistent renal Fanconi syndrome and congenital cataracts, and maternal carrier status was confirmed in the majority of pedigrees (PMID:27708066).

The inheritance mode is X-linked recessive, with pathogenic variants found across all functional domains of OCRL. The variant spectrum includes at least 80 missense changes, 90 truncating mutations (nonsense and frameshift), and >30 splice-site alterations. A recurrent splice-donor mutation, c.2256+1G>T (IVS19+1G>T), disrupts normal intron 19 splicing, abolishing phosphatase activity and correlating with progressive renal failure and FSGS in adult patients (PMID:14981612).

Functional studies demonstrate that OCRL loss leads to accumulation of phosphatidylinositol-4,5-bisphosphate on endosomes, aberrant N-WASP–driven F-actin polymerization, and impaired endosomal trafficking of multiligand receptors such as megalin, providing a molecular basis for renal Fanconi syndrome (PMID:21971085). Patient-derived fibroblasts exhibit defective cell migration and membrane ruffling, which is rescued by wild-type but not phosphatase-dead OCRL, confirming a loss-of-function mechanism (PMID:19700499).

Some OCRL variants yield overlapping phenotypes with Dent disease 2 (MONDO:0010359); intronic mutations causing incomplete exon skipping produce residual OCRL expression and milder renal-only presentations, illustrating phenotypic continuum and the impact of alternative splicing on disease severity (PMID:32427950).

In summary, OCRL is definitively associated with the oculocerebrorenal syndrome of Lowe, supported by extensive case series, segregation across multiple pedigrees, and concordant cell-biological deficits. Genetic testing for OCRL variants is essential for early diagnosis, family counseling, and management of renal, ocular, and neurodevelopmental complications.

Key take-home: Recognition of characteristic OCRL variants enables definitive diagnosis of Lowe syndrome, guiding multidisciplinary care and advancing therapeutic strategies.

References

• American journal of human genetics • 1997 • Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome PMID:9199559
• Ophthalmology and kidney diseases • 2004 • Advanced renal insufficiency in a 34-year-old man with Lowe syndrome PMID:14981612
• Nephrology, dialysis, transplantation • 2018 • Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort PMID:27708066
• The EMBO journal • 2011 • OCRL controls trafficking through early endosomes via PtdIns4,5P2-dependent regulation of endosomal actin PMID:21971085
• Human molecular genetics • 2009 • Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase PMID:19700499

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