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Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects
Stephanie M Ware1, Jianlan Peng, Lirong Zhu
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Insights
Zinc finger transcription factor ZIC3 mutations are linked to X-linked heterotaxy and congenital heart disease (CHD). This study expands the known ZIC3 mutation spectrum, identifying novel mutations and providing insights into disease mechanisms.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Biology
Background:
- Mutations in ZIC3, a zinc finger transcription factor, are known to cause X-linked heterotaxy.
- ZIC3 mutations have also been observed in individuals with isolated congenital heart disease (CHD).
Purpose of the Study:
- To investigate the role of ZIC3 mutations in both heterotaxy and isolated CHD.
- To determine the frequency and spectrum of ZIC3 mutations in a patient cohort.
Main Methods:
- Screening of the ZIC3 coding region in 194 unrelated patients with heterotaxy or CHD.
- Genotyping of 97 ethnically matched control samples.
- Functional analysis of identified ZIC3 mutations using reporter gene assays and transfection studies.
Main Results:
- Five novel ZIC3 mutations were identified in patients with heterotaxy and sporadic CHD.
- ZIC3 mutations were found in approximately 1% of sporadic heterotaxy cases.
- Mutations affected the DNA binding domain and N-terminal domain, leading to loss of transactivation and, in some cases, aberrant cytoplasmic localization.
Conclusions:
- The phenotypic spectrum of ZIC3 mutations should be broadened to include affected females and CHD not typical of heterotaxy.
- ZIC3 mutations contribute to a subset of sporadic heterotaxy and CHD cases.
- Pathogenesis involves impaired DNA binding and abnormal nuclear localization of the ZIC3 protein.
Abstract:
Mutations in the zinc finger transcription factor ZIC3 cause X-linked heterotaxy and have also been identified in patients with isolated congenital heart disease (CHD). To determine the relative contribution of ZIC3 mutations to both heterotaxy and isolated CHD, we screened the coding region of ZIC3 in 194 unrelated patients, including 61 patients with classic heterotaxy, 93 patients with heart defects characteristic of heterotaxy, and 11 patients with situs inversus totalis. Five novel ZIC3 mutations in three classic heterotaxy kindreds and two sporadic CHD cases were identified. None of these alleles was found in 97 ethnically matched control samples. On the basis of these analyses, we conclude that the phenotypic spectrum of ZIC3 mutations should be expanded to include affected females and CHD not typical for heterotaxy. This screening of a cohort of patients with sporadic heterotaxy indicates that ZIC3 mutations account for approximately 1% of affected individuals. Missense and nonsense mutations were found in the highly conserved zinc finger-binding domain and in the N-terminal protein domain. Functional analysis of all currently known ZIC3 point mutations indicates that mutations in the putative zinc finger DNA binding domain and in the N-terminal domain result in loss of reporter gene transactivation. It is surprising that transfection studies demonstrate aberrant cytoplasmic localization resulting from mutations between amino acids 253-323 of the ZIC3 protein, indicating that the pathogenesis of a subset of ZIC3 mutations results at least in part from failure of appropriate nuclear localization. These results further expand the phenotypic and genotypic spectrum of ZIC3 mutations and provide initial mechanistic insight into their functional consequences.
