Heterotaxy and cardiac defect in a girl with chromosome translocation t(X;1)(q26;p13.1) and involvement of ZIC3

Tzschach, Andreas; Hoeltzenbein, Maria; Hoffmann, Katharina; Menzel, Corinna; Beyer, Alexander; Ocker, V.; Wurster, Goetz; Raynaud, Martine; Ropers, Hans‐Hilger; Kalscheuer, Vera M.; Heilbronner, H.

doi:10.1038/sj.ejhg.5201707

Cited by 17 publications

(14 citation statements)

References 9 publications

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“…2 3 5 19 In our patient an insertion of GCCGCC in exon 1 of the ZIC3 gene was identified. This mutation maintains the wild-type reading frame and codes for two additional alanines in the polyalanine stretch of ZIC3.…”

Section: Discussionmentioning

confidence: 58%

Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?

Wessels

Kuchinka

Heydanus

et al. 2010

Journal of Medical Genetics

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It is hypothesized that this novel and de novo polyalanine expansion in ZIC3 contributes to the VACTERL association in this patient. A newborn male is described with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-oesophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. As the clinical picture of the VACTERL association overlaps with X-linked heterotaxy caused by ZIC3 mutations, the ZIC3 coding region was sequenced, and a 6-nucleotide insertion was found that is predicted to expand the amino-terminal polyalanine repeat from 10 to 12 polyalanines. This novel mutation was not present in the mother, nor in 336 chromosomes from 192 ethnically matched controls. It is hypothesised that this novel and de novo polyalanine expansion in the ZIC3 gene contributes to the VACTERL association in this patient.

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Section: Discussionmentioning

confidence: 58%

Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?

Wessels

Kuchinka

Heydanus

et al. 2010

Journal of Medical Genetics

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“…This is opposite to the cases where the disruption of the ZIC3 gene was the result of X-autosome translocation. In these cases there will be functional nullisomy and the female carriers have severe phenotype [Fritz et al, 2005;Tzschach et al, 2006].…”

Section: Discussionmentioning

confidence: 99%

From VACTERL‐H to heterotaxy: Variable expressivity of ZIC3—related disorders

Chung

Shaffer

Keating

et al. 2011

American J of Med Genetics Pt A

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The ZIC3 gene encodes a zinc finger protein which functions as a transcription factor in early stages of left-right body axis formation. Mutations in this X-linked gene cause a variety of clinical manifestations including heterotaxy, complex or isolated heart defect as well as other midline urogenital and hindgut malformations. We report a four generation family with X-linked heterotaxy associated with a deletion of the ZIC3 gene at Xq26.3. The index fetus of our proband showed classical features of heterotaxy while her maternal uncle and one brother had imperforate anus and her other brother had features suggestive of VACTERL-H without heterotaxy. A 1.4 Mb deletion in Xq26.3 including the ZIC3 gene was found in the fetus. Six females in the family were found to be asymptomatic carriers. Our report indicates that some of the cases with VACTERL-H syndrome may be caused by a mutation or deletion of the ZIC3 gene.

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“…ZIC3 mutations have also been reported in patients with isolated cardiovascular malformations [Megarbane et al, 2000;Ware et al, 2004]. Additional deletion alleles, a recently described missense allele, and a case of X-autosome translocation reinforce the important role of this gene in left-right patterning and multiple congenital anomalies [Casey et al, 1993;Chhin et al, 2007;Mathias et al, 1987;Tzschach et al, 2006]. However, the pathogenesis of these mutations remains largely unknown.…”

Section: Zic3 (Mim] 300265mentioning

confidence: 97%

Characterization of the interactions of human ZIC3 mutants with GLI3

Zhu¹,

Zhou²,

Poole³

et al. 2007

Hum. Mutat.

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ZIC3, a GLI superfamily transcription factor, is involved in establishing normal embryonic left-right patterning. Multiple abnormalities in the central nervous system (CNS) and axial skeleton have also been observed in mice bearing a Zic3 null allele, mice with a Zic3 overexpression allele, and the majority of patients carrying ZIC3 mutations. Previous studies indicate that ZIC3 protein can bind to the GLI consensus binding site (GLIBS) and physically interact with GLI3, a transcription factor involved in multiple aspects of neural and skeletal development. We investigated in vitro interactions of ZIC3 with GLI3 and the effect of ZIC3 mutations identified in patients with either heterotaxy or isolated cardiovascular malformations. Electrophoresis mobility shift assay (EMSA) revealed that all five intact zinc finger (ZF) domains were necessary for binding of ZIC3 to GLIBS. Inclusion of GLIBS upstream of a basal TK promoter had no effect on the activation of the promoter by ZIC3 alone, but it enhanced the synergistic activation of ZIC3 and GLI3. Wild-type (WT) ZIC3 showed specific binding to GLI3 in GST-pull-down assays. Nonsense and frameshift ZIC3 mutants lacking one or more of the zinc finger domains did not physically interact with GST-GLI3; however, two missense mutants c.1213A>G (p.K405E, fifth ZF domain), and c.649C>G (p.P217A, conserved N-terminal domain) retained binding. Luciferase reporter assays indicated that both p.P217A and p.K405E mutants also retained coactivation with GLI3 of reporter gene expression activity, while all the GLI3-nonbinding ZIC3 mutants lacked this activity. Interestingly, no CNS or skeletal abnormalities were observed in patients bearing the p.P217A or p.K405E mutations.

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Heterotaxy and cardiac defect in a girl with chromosome translocation t(X;1)(q26;p13.1) and involvement of ZIC3

Cited by 17 publications

References 9 publications

Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?

Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?

From VACTERL‐H to heterotaxy: Variable expressivity of ZIC3—related disorders

Characterization of the interactions of human ZIC3 mutants with GLI3

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