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A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies.
Am J Med Genet A. 2017 Dec; 173(12):3221-3225.AJ

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.

Authors+Show Affiliations

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California.Division of Medical Genetics, Stanford University School of Medicine, Stanford, California.Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California. Department of Developmental Biology, Stanford University School of Medicine, Stanford, California.Division of Medical Genetics, Stanford University School of Medicine, Stanford, California.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28884880

Citation

Crapster, J Aaron, et al. "A Novel Missense Variant in the GLI3 Zinc Finger Domain in a Family With Digital Anomalies." American Journal of Medical Genetics. Part A, vol. 173, no. 12, 2017, pp. 3221-3225.
Crapster JA, Hudgins L, Chen JK, et al. A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies. Am J Med Genet A. 2017;173(12):3221-3225.
Crapster, J. A., Hudgins, L., Chen, J. K., & Gomez-Ospina, N. (2017). A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies. American Journal of Medical Genetics. Part A, 173(12), 3221-3225. https://doi.org/10.1002/ajmg.a.38415
Crapster JA, et al. A Novel Missense Variant in the GLI3 Zinc Finger Domain in a Family With Digital Anomalies. Am J Med Genet A. 2017;173(12):3221-3225. PubMed PMID: 28884880.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies. AU - Crapster,J Aaron, AU - Hudgins,Louanne, AU - Chen,James K, AU - Gomez-Ospina,Natalia, Y1 - 2017/09/08/ PY - 2017/01/10/received PY - 2017/07/24/revised PY - 2017/07/29/accepted PY - 2017/9/9/pubmed PY - 2018/3/22/medline PY - 2017/9/9/entrez KW - GLI3 KW - greig cephalopolysyndactyly KW - pallister-hall KW - polydactyly KW - zinc finger domain SP - 3221 EP - 3225 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 173 IS - 12 N2 - 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/28884880/A_novel_missense_variant_in_the_GLI3_zinc_finger_domain_in_a_family_with_digital_anomalies_ L2 - https://doi.org/10.1002/ajmg.a.38415 DB - PRIME DP - Unbound Medicine ER -