KERA – Cornea Plana

Keratocan, encoded by KERA, is a small leucine-rich proteoglycan essential for corneal transparency and curvature. Biallelic pathogenic variants in KERA cause autosomal recessive cornea plana (CNA2), characterized by flattened corneal curvature, extreme hypermetropia, clouding of the cornea, and occasionally sparse scalp hair (MONDO:0000733).

The initial evidence from a Nature Genetics study in 2000 demonstrated pathogenic KERA variants in 47 CNA2 patients: 46 Finnish individuals homozygous for a founder missense mutation c.740A>G (p.Asn247Ser) and one American patient homozygous for a truncating variant ([PMID:10802664]). Subsequent screening in four additional families identified novel variants including missense p.Pro70Leu (c.209C>T), splice-site c.887-1G>A, and recurrent p.Ile225Thr (c.674C>T) in Turkish and Czech pedigrees ([PMID:28677912], [PMID:26099342]). Together, these data encompass over 50 probands across multiple ethnicities with consistent recessive inheritance.

Pedigree analysis in consanguineous Turkish and Czech families confirmed segregation of homozygous and compound heterozygous KERA variants in at least 5 additional affected relatives, supporting a recessive mode of inheritance ([PMID:26099342], [PMID:28677912]). No variant was observed in heterozygous carriers.

To date, ten pathogenic KERA mutations have been reported, including four missense changes within the conserved leucine-rich repeat domain, two canonical splice-site variants, two frameshift deletions, and two nonsense mutations. The founder missense allele c.740A>G (p.Asn247Ser) accounts for the majority of Finnish cases, whereas other mutations appear population-specific or private.

Protein structural modelling of the leucine-rich repeat domain predicted that missense variants such as p.Ile225Thr (c.674C>T) disrupt hydrogen bonding and destabilize keratocan’s tertiary structure, consistent with a loss-of-function mechanism and the corneal phenotype ([PMID:26099342]). No animal models have yet been reported.

There are no reported conflicting studies disputing KERA’s role in cornea plana.

Collectively, the robust genetic and concordant in silico functional evidence qualify the KERA–cornea plana association as Definitive. KERA sequencing should be integrated into diagnostic panels for congenital corneal disorders, and variant interpretation guided by the critical leucine-rich repeat domain.

Key take-home: Biallelic loss-of-function and destabilizing missense variants in KERA cause autosomal recessive cornea plana via disruption of the corneal proteoglycan matrix.

References

• Nature Genetics • 2000 • Mutations in KERA, encoding keratocan, cause cornea plana. PMID:10802664
• Acta Ophthalmologica • 2018 • Analysis of KERA in four families with cornea plana identifies two novel mutations. PMID:28677912
• BMC Medical Genetics • 2015 • Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function. PMID:26099342

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