Zhao et al. 2015 — Lanosterol and cataract protein aggregation
TL;DR
This paper supplied the original experimental rationale for lanosterol as an anti-cataract lead. The authors identified homozygous G588S and W581R mutations in lanosterol synthase (LSS) in two consanguineous families with congenital cataracts, reported that wild-type LSS expression or exogenous lanosterol reduced aggregation in engineered crystallin systems, and reported paired improvements in isolated rabbit cataractous lenses and a canine in-vivo analysis.1 The human evidence was family genetics, not treatment; the main article did not show that topical lanosterol treats age-related cataract in people. gap/needs-human-replication gap/needs-replication
Design
The study combined:
- Human family genetics: whole-exome sequencing in a consanguineous family with three affected children identified homozygous G588S. Screening LSS in 154 congenital-cataract families found homozygous W581R in one affected member of a second consanguineous family. Figure 1 shows parental segregation, and both variants were absent from 11,000 control chromosomes.
- Enzyme and cell assays: wild-type and mutant LSS were expressed in cultured cells; six cataract-causing mutant crystallins were tested across human lens progenitor cells, HLEB-3 cells, or HeLa cells. Most plotted comparisons used three independent samples. The serial live-cell experiment used 22 observations from three biological replicates.
- Purified-protein assays: aggregates prepared from five wild-type and nine mutant crystallins under guanidine/heat stress were exposed to lanosterol or cholesterol in dipalmitoyl-phosphatidylcholine liposomes and assessed by thioflavin-T fluorescence and electron microscopy.
- Rabbit lenses: naturally occurring cataractous lenses were isolated and incubated in 25 mM lanosterol solution for six days. Figure 5 reports
n=13lenses; the number of source rabbits, vehicle composition, and control allocation are not stated in the main article. - Canine experiment: in-vivo treatment was followed by paired cataract grading. Figure 5 reports
n=7, but the main article does not define whether this count denotes dogs, eyes, or lenses and does not state the administration route, formulation, dose, schedule, control allocation, or masking. gap/needs-supp-verification
Because these systems use different experimental units, n-subjects: null is intentional; summing them would be misleading.
Key findings verified in the main article
- The G588S pedigree contained three affected homozygous children; the W581R pedigree contained one affected homozygote. Wild-type LSS increased cellular lanosterol, whereas neither mutant showed cyclase activity (
n=3per group); cellular cholesterol was unchanged.1 - Wild-type, but not mutant, LSS reduced the number and size of intracellular aggregates formed by cataract-causing mutant crystallins. Exogenous lanosterol produced concentration-dependent reductions at 10—40 micromolar in the reported cell assay, whereas cholesterol did not. The live-cell fluorescence-decay fit yielded 222 ± 8 minutes (
n=22observations from three biological replicates).1 - Lanosterol, but not cholesterol, reduced thioflavin-T signal and fibrillar structures in artificially generated crystallin aggregates. These guanidine/heat-induced preparations were model aggregates, not intact human cataracts.1
- Isolated rabbit cataractous lenses showed a paired improvement in clarity/grade after six days in 25 mM lanosterol (
n=13lenses, Wilcoxon P<0.003). The canine paired analysis also showed a lower cataract stage after treatment (n=7analysis units, Wilcoxon P<0.009). Neither experiment measured human visual function.1
Interpretation and limitations
The family data linked biallelic loss-of-function LSS variants to congenital cataract in four affected people across two pedigrees, while the experimental systems supplied a plausible connection among LSS, lanosterol, and crystallin aggregation. They did not establish ocular exposure or efficacy of an eye-drop formulation in the aged human lens.
The main article’s animal evidence is limited to paired pre/post grading and photographs plus the stated P values. Without the unavailable Online Methods, Extended Data, and Source Data, this verification cannot establish the animal vehicle/control design, randomization or masking, grading reproducibility, dog sample unit, administration route, or exposure. The canine experiment therefore must not be described specifically as topical or as an eye-drop study on the basis of the main article alone. gap/needs-supp-verification
Later human-lens and rat-lens experiments failed to reproduce macroscopic clearing under their conditions; see shanmugam-2015-lanosterol-human-cataract-nuclei and daszynski-2019-lanosterol-failure. Other later preclinical work reported model- and subtype-dependent positive signals, including transient cortical but little nuclear improvement in three monkeys per subtype; see zhang-2022-lanosterol-cynomolgus-cataracts. No published human therapeutic trial or meta-analysis superseded the preclinical evidence through 2026-08-18. The mixed results make formulation, delivery, cataract subtype, disease stage, and model selection central unresolved variables. gap/contradictory-evidence
Nature issued a 2015 corrigendum assigning Yong-Bin Yan to affiliation 4 rather than affiliation 5; it did not correct the study data or conclusions.2
Extrapolation to humans
| Dimension | Status | Notes |
|---|---|---|
| Pathway conserved in humans? | yes | Human LSS variants and human-derived crystallin cell systems were part of the study. |
| Phenotype conserved in humans? | partial | Protein aggregation is shared, but congenital and age-related cataracts are not interchangeable. |
| Replicated in humans? | no | No therapeutic human arm was performed. |
Cited by wiki pages
[Auto-populated by Obsidian backlinks]
Footnotes
-
Zhao L, Chen XJ, Zhu J, Xi YB, Yang X, et al. · doi:10.1038/nature14650 · PMID:26200341 · Nature 2015;523(7562):607—611 · human congenital-cataract pedigrees plus cell, purified-protein, isolated-rabbit-lens, and canine in-vivo experiments · main article verified; Online Methods, Extended Data Figures/Tables, and Source Data unavailable. ↩ ↩2 ↩3 ↩4 ↩5
-
doi:10.1038/nature15253 · Nature 2015;526:595 · affiliation-only corrigendum for Yong-Bin Yan; no data or conclusion change. ↩