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A novel frameshift mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome using targeted exome sequencing.
BMC Med Genet. 2019 06 11; 20(1):105.BM

Abstract

BACKGROUND

Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS.

METHODS

An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls.

RESULTS

All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls.

CONCLUSIONS

PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.

Authors+Show Affiliations

Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China.Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China.Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China.Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China.Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China.Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China.Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China.Department of Ophthalmology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, 410011, Hunan, People's Republic of China. sjm93cn@csu.edu.cn. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, People's Republic of China. sjm93cn@csu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31185933

Citation

Zhang, Lusi, et al. "A Novel Frameshift Mutation in the PITX2 Gene in a Family With Axenfeld-Rieger Syndrome Using Targeted Exome Sequencing." BMC Medical Genetics, vol. 20, no. 1, 2019, p. 105.
Zhang L, Peng Y, Ouyang P, et al. A novel frameshift mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome using targeted exome sequencing. BMC Med Genet. 2019;20(1):105.
Zhang, L., Peng, Y., Ouyang, P., Liang, Y., Zeng, H., Wang, N., Duan, X., & Shi, J. (2019). A novel frameshift mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome using targeted exome sequencing. BMC Medical Genetics, 20(1), 105. https://doi.org/10.1186/s12881-019-0840-9
Zhang L, et al. A Novel Frameshift Mutation in the PITX2 Gene in a Family With Axenfeld-Rieger Syndrome Using Targeted Exome Sequencing. BMC Med Genet. 2019 06 11;20(1):105. PubMed PMID: 31185933.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel frameshift mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome using targeted exome sequencing. AU - Zhang,Lusi, AU - Peng,Yingqian, AU - Ouyang,Pingbo, AU - Liang,Youling, AU - Zeng,Huilan, AU - Wang,Nuo, AU - Duan,Xuanchu, AU - Shi,Jingming, Y1 - 2019/06/11/ PY - 2018/10/08/received PY - 2019/06/04/accepted PY - 2019/6/13/entrez PY - 2019/6/13/pubmed PY - 2019/10/1/medline KW - Axenfeld-Rieger syndrome KW - Frameshift variation KW - PITX2 KW - Targeted exome sequencing SP - 105 EP - 105 JF - BMC medical genetics JO - BMC Med. Genet. VL - 20 IS - 1 N2 - BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. METHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. RESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. CONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript. SN - 1471-2350 UR - https://www.unboundmedicine.com/medline/citation/31185933/A_novel_frameshift_mutation_in_the_PITX2_gene_in_a_family_with_Axenfeld-Rieger_syndrome_using_targeted_exome_sequencing L2 - https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-019-0840-9 DB - PRIME DP - Unbound Medicine ER -