ZNF469 – Brittle Cornea Syndrome 1

Brittle cornea syndrome 1 (BCS1) is a rare autosomal recessive connective tissue disorder characterized by extreme corneal thinning, fragility leading to rupture, progressive visual loss, and multisystem involvement including hearing impairment and skeletal features. The ZNF469 gene (HGNC:23216), encoding a zinc-finger protein with homology to collagens, has been implicated as the causative gene for BCS1 (PMID:18452888). Since the initial discovery, biallelic ZNF469 variants have been reported in diverse populations, confirming its central role in BCS1 pathogenesis.

Genetic evidence for ZNF469 in BCS1 includes over 53 unrelated patients across more than 23 families, with homozygous or compound heterozygous loss-of-function and missense mutations consistent with autosomal recessive inheritance (PMID:33739556). Key cohorts comprise five unrelated Tunisian Jewish patients (PMID:18452888), a consanguineous Pakistani family with four affected individuals (PMID:30865045), and Spanish siblings harboring a novel homozygous frameshift variant (PMID:37098112). Additional case reports, including a Czech/Polish compound heterozygote (PMID:31025659) and two sisters with mild BCS1, further expand the allelic spectrum.

Segregation analyses in these families demonstrate clear co-segregation of ZNF469 variants with disease in at least 19 affected relatives across multiple pedigrees, supporting high penetrance in biallelic carriers. The mutational spectrum comprises frameshift, nonsense, splice, and critical cysteine-to-tyrosine missense substitutions affecting zinc-finger domains, exemplified by c.10016G>A (p.Cys3339Tyr) in affected homozygotes (PMID:19661234). Recurrent founder alleles have been noted in population isolates, while various private mutations account for sporadic and consanguineous cases.

Functional studies indicate that ZNF469 acts as a transcriptional regulator of extracellular matrix components, particularly fibrillar collagens, essential for corneal and connective tissue integrity. Loss-of-function mutations result in disrupted collagen fibrillogenesis and altered corneal thickness in vitro and in vivo models, aligning with the human phenotype. Furthermore, ZNF469 and PRDM5 participate in the same regulatory pathway, reinforcing mechanistic concordance (PMID:21664999).

Mechanistically, pathogenic ZNF469 variants likely cause disease through haploinsufficiency or dominant-negative effects on zinc-finger domains critical for DNA binding and collagen gene regulation. The resulting extracellular matrix defects manifest as corneal fragility, blue sclerae, joint hypermobility, scoliosis, and sensorineural hearing loss. Ongoing research into collagen organization pathways may elucidate targeted therapeutic strategies.

Although rare heterozygous ZNF469 variants have been proposed in keratoconus, a case–control study in Polish patients found no significant enrichment of deleterious variants in keratoconus compared to controls, arguing against a primary role outside BCS1 (PMID:26806788). No other conflicting evidence disputes the robust association between biallelic ZNF469 variants and BCS1.

In summary, the ZNF469–BCS1 association is supported by definitive genetic validity with consistent autosomal recessive segregation, diverse loss-of-function variants, and complementary functional data demonstrating extracellular matrix dysregulation. Comprehensive gene panels including ZNF469 enable timely diagnosis, carrier detection, and preventive measures for vision and skeletal complications. Key take-home: biallelic ZNF469 mutations cause brittle cornea syndrome type 1, and early molecular diagnosis informs clinical management and genetic counseling.

References

• American journal of human genetics • 2008 • Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome PMID:18452888
• Investigative Ophthalmology & Visual Science • 2010 • Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene PMID:19661234
• Cornea • 2019 • Identification of a Novel ZNF469 Mutation in a Pakistani Family With Brittle Cornea Syndrome PMID:30865045
• Cornea • 2023 • New ZNF469 Mutations in Spanish Siblings With Brittle Cornea Syndrome PMID:37098112
• Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia • 2020 • Brittle cornea syndrome: Disease-causing mutations in ZNF469 and two novel variants identified in a patient followed for 26 years PMID:31025659
• Human mutation • 2021 • More than meets the eye: Expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome PMID:33739556

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