Novel PITX2 gene mutations in patients with Axenfeld-Rieger syndrome

作者：Seifi Morteza; Footz Tim; Taylor Sherry A M; Elhady Ghada M; Abdalla Ebtesam M; Walter Michael A^*

来源：Acta Ophthalmologica, 2016, 94(7): E571-E579.

DOI：10.1111/aos.13030

• chromosome 4q25
• compound heterozygote
• deletion
• glaucoma
• transcription factor

PurposeMutations in the bicoid-like transcription factor PITX2 gene often result in Axenfeld-Rieger syndrome (ARS), an autosomal-dominant inherited disorder. We report here the discovery and characterization of novel PITX2 deletions in a small kindred with ARS.
MethodsTwo familial patients (father and son) from a consanguineous family were examined in the present study. Patient DNA samples were screened for PITX2 mutations by DNA sequencing and for copy number variation by SYBR Green quantitative polymerase chain reaction (PCR) analysis.
ResultsWe report a novel deletion involving the coding region of PITX2 in both patients. The minimum size of the deletion is 1421914bp that spans one upstream regulatory element (CE4), PITX2 and a minimum of 13 neighbouring genes. The maximum size of the deletion is 3789983bp. The proband (son) additionally possesses a novel 2-bp deletion in a non-coding exon of the remaining PITX2 allele predicted to alter correct splicing.
ConclusionOur findings implicate a novel deletion of the PITX2 gene in the pathogenesis of ARS in the affected family. This ARS family presented with an atypical and extremely severe phenotype that resulted in four miscarriages and the death at 10months of age of a sib of the proband. As the phenotypic manifestations in the proband are more severe than that of the father, we hypothesize that the deletion of the entire PITX2 allele plus a novel 2-bp deletion (observed in the proband) within the remaining PITX2 allele together contributed to the atypical ARS presentation in this family. This is the first study reporting on bi-allelic changes of PITX2 potentially contributing to a more severe ARS phenotype.

• 出版日期2016-11