Disease relevance of KERA

• Among them, keratocan mRNA transcript and protein were demonstrated to be expressed at a higher level specifically in the keratoconus stroma [1].

High impact information on KERA

• Here we report mutations in KERA in 47 CNA2 patients: 46 Finnish patients are homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid; and one American patient is homozygous for a mutation leading to a premature stop codon that truncates the KERA protein [2].
• By linkage analysis this phenotype was mapped to the immediate vicinity of markers D12S82 and D12S351 on 12q, that is, precisely the same small region (3 cM or less) to which CNA2 previously had been assigned [3].
• We recently assigned a CNA2 locus to a region on chromosome 12 by linkage analysis and excluded linkage to that locus in two Finnish CNA1 families [3].
• The Kera gene is expressed in ocular surface tissues including cornea and eyelids during morphogenesis [4].
• This phenotypic change in activated corneal stromal cells is induced by bFGF/HS and by TGF-beta1, and it accompanies the downregulation of keratocan expression [5].

Biological context of KERA

• Normal corneal function is dependent on the regular spacing of collagen fibrils, and the predicted alteration of the tertiary structure of KERA is the probable mechanism of the cornea plana phenotype [6].
• Assignment of keratocan gene (KERA) to human chromosome band 12q22 by in situ hybridization [7].
• CONCLUSIONS: This novel point mutation in KERA is the fourth thus far described [8].
• RESULTS: Positive lod scores were obtained with markers encompassing the CNA2 locus, the maximum two-point lod scores of 2.18 at recombination fraction theta = 0 was obtained with markers D12S95 and D12S327 [6].
• In addition, a conserved CArG-box residing 851 bp upstream of the first transcription start site also can lead to the repression of Kera expression in cultured corneal keratocytes [9].

Anatomical context of KERA

• Keratocan expression is increased in the stroma of keratoconus corneas [1].
• Lumican and keratocan are members of the small leucine-rich proteoglycan (SLRP) family, and are the major keratan sulfate (KS) proteoglycans in corneal stroma [10].
• Human keratocytes cultured on amniotic membrane stroma preserve morphology and express keratocan [11].
• Fibroblasts continuously cultured on plastic to passages 3 and 11 did not reverse their morphology or synthesize keratocan when reseeded on plastic in 1% FBS or on AM [11].

Associations of KERA with chemical compounds

• Mutation screening of KERA revealed a novel single-nucleotide substitution at codon 215, which results in the substitution of lysine for threonine at the start of a highly conserved leucine-rich repeat motif [6].
• Other mutations in KERA known to cause cornea plana also fall within the region encoding the leucine-rich repeat motifs and are predicted to affect the tertiary structure of the protein [12].
• Keratocan, along with lumican and mimecan, represent the keratan sulfate-containing proteoglycans of the vertebrate cornea that play a key role in development and maintenance of corneal transparency [9].
• This mutation leads to replacement of an arginine by a stop codon at position 313 of keratocan protein [8].
• The correlations (r) between c(2 h) and CNA 2 h postdose were as follows: CsA, r = -0.74; CsA+MMF, r = -0.84; TRL, r = -0.70; TRL+ MMF, r = -0.70 (P <0.001 in all cases) [13].

Other interactions of KERA

• In wounded corneas or when cultured in the presence of serum to mimic wound-healing responses, keratocytes underwent fibroblastic transformation (with appearance of alpha-SMA and disappearance of CD-34 and keratocan signals) and started expressing VSX1 [14].

Analytical, diagnostic and therapeutic context of KERA

• CONCLUSIONS: Keratocan expression in the stoma was increased in keratoconus corneas [1].
• The role of lumican and keratocan genes in persistent subepithelial corneal haze following excimer laser photorefractive keratectomy [15].
• Both lumican and keratocan are essential for normal cornea morphogenesis during embryonic development and maintenance of corneal topography in adults [10].
• Northern and Western blotting and immunohistochemical analysis showed that no Kera mRNA or keratocan protein was detected in the Kera-/- cornea [4].
• As demonstrated by transmission electron microscopy, Kera-/- mice have larger stromal fibril diameters and less organized packing of collagen fibrils in stroma than those of wild type [4].

References