title: Extremely varied phenotypes in granular corneal dystrophy type 2 heterozygotes.
abstract: OBJECTIVE
  To investigate the phenotypic variability of patients bearing the heterozygous R124H mutation in the TGFBI (transforming growth factor-beta-induced) gene that causes granular corneal dystrophy type 2 (GCD2).
  
  
  METHODS
  We describe the phenotypic range of GCD2 heterozygotes for the common R124H mutation in TGFBI; seven with an extremely mild phenotype and six with an extremely severe phenotype. Detailed slit-lamp photographs of these patients were generated. All patients had no history of ocular surgery and were diagnosed as being heterozygous for GCD2 by DNA analysis from peripheral blood. Expression levels of transforming growth factor-beta-induced protein (TGFBIp) were compared among cultured corneal fibroblasts from ten normal donors.
  
  
  RESULTS
  We report profound differences in the severity of the phenotype across our case series. Two patients with a mild phenotype were diagnosed as unaffected at presentation; however follow-up examinations revealed granular deposits. Importantly, we also observed familial clustering of phenotypic variance; five patients from two families with a mild phenotype showed a similarly mild phenotype within family members. Similarly, six patients from two families with severe phenotypes showed corneal deposits with similar patterns and severity within each distinct family, but distinct patterns between families. TGFBIp expressions from different donor derived cultured corneal fibroblasts were different between one another.
  
  
  CONCLUSIONS
  GCD2 heterozygotes have extremely varied phenotypes between individual patients. However phenotypes were broadly consistent within families, suggesting that the observed variable expressivity might be regulated by other genetic factors that could influence the abundance of TGFBIp or the function of the pathway. From a clinical perspective, our data also highlighted that genetic analysis and meticulous slit-lamp examination in both eyes at multiple time intervals is necessary.
authors: Corneal Dystrophy Research Institute, Yonsei University College of Medicine, 50 Yonseiro,Seodaemun-gu, Seoul, Korea.
authors: Kyung Eun
authors: KE
authors: Han
authors: Seung-il
authors: SI
authors: Choi
authors: Woo Suk
authors: WS
authors: Chung
authors: Se Hwan
authors: SH
authors: Jung
authors: Nicholas
authors: N
authors: Katsanis
authors: Tae-im
authors: TI
authors: Kim
authors: Eung Kweon
authors: EK
authors: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism* / Q000473:pathology; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein