title: Functional analysis of human mutations in homeodomain transcription factor PITX3.
abstract: BACKGROUND
  The homeodomain-containing transcription factor PITX3 was shown to be essential for normal eye development in vertebrates. Human patients with point mutations in PITX3 demonstrate congenital cataracts along with anterior segment defects in some cases when one allele is affected and microphthalmia with brain malformations when both copies are mutated. The functional consequences of these human mutations remain unknown.
  
  
  RESULTS
  We studied the PITX3 mutant proteins S13N and G219fs to determine the type and severity of functional defects. Our results demonstrate alterations in DNA-binding profiles and/or transactivation activities and suggest a partial loss-of-function in both mutants with the G219fs form being more severely affected. No anomalies in cellular distribution and no dominant-negative effects were discovered for these mutants. Interestingly, the impairment of the G219fs activity varied between different ocular cell lines.
  
  
  CONCLUSIONS
  The G219fs mutation was found in multiple families affected with congenital cataracts along with anterior segment malformations in many members. Our data suggest that the presence/severity of anterior segment defects in families affected with G219fs may be determined by secondary factors that are expressed in the developing anterior segment structures and may modify the effect(s) of this mutation. The S13N mutant showed only minor alteration of transactivation ability and DNA binding pattern and may represent a rare polymorphism in the PITX3 gene. A possible contribution of this mutation to human disease needs to be further investigated.
authors: Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. saka377@gcmc.pref.gunma.jp
authors: Satoru
authors: S
authors: Sakazume
authors: Elena
authors: E
authors: Sorokina
authors: Yoshiki
authors: Y
authors: Iwamoto
authors: Elena V
authors: EV
authors: Semina
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000869:Anterior Eye Segment / Q000473:pathology; D001483:Base Sequence; D002386:Cataract / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004285:Dogs; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005801:Genes, Homeobox / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007908:Lens, Crystalline / Q000473:pathology; D051379:Mice; D008850:Microphthalmos / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009421:Nervous System Malformations / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D051381:Rats; D016415:Sequence Alignment; D017385:Sequence Homology; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D005819:Genetic Markers; D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3