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A Novel Missense Variant in the GLI3 Zinc Finger Domain in a Family with Digital Anomalies
- Publication Year :
- 2017
-
Abstract
- Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3-related phenotype. Given the complexity of GLI3 post-translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed GLI3 variants. This family also demonstrates how GLI3 variants are variably expressed.
- Subjects :
- 0301 basic medicine
musculoskeletal diseases
congenital, hereditary, and neonatal diseases and abnormalities
animal structures
Genotyping Techniques
Mutation, Missense
Repressor
Nerve Tissue Proteins
030105 genetics & heredity
Biology
Article
Fingers
03 medical and health sciences
Mice
Genes, Reporter
Zinc Finger Protein Gli3
GLI2
GLI3
Genetics
medicine
Missense mutation
Animals
Humans
Amino Acid Sequence
Genetics (clinical)
Zinc finger
Polydactyly
Preaxial polydactyly
Zinc Fingers
Sequence Analysis, DNA
Acrocephalosyndactylia
Fibroblasts
Toes
medicine.disease
Hedgehog signaling pathway
Pedigree
body regions
Repressor Proteins
030104 developmental biology
Phenotype
Thumb
Child, Preschool
embryonic structures
Female
Sequence Alignment
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....195ec0235df155896770016b9f7dd4ba