ZFIN ID: ZDB-PUB-160715-5
Rare novel variants in the ZIC3 gene cause X-linked heterotaxy
Paulussen, A.D., Steyls, A., Vanoevelen, J., van Tienen, F.H., Krapels, I.P., Claes, G.R., Chocron, S., Velter, C., Tan-Sindhunata, G.M., Lundin, C., Valenzuela, I., Nagy, B., Bache, I., Maroun, L.L., Avela, K., Brunner, H.G., Smeets, H.J., Bakkers, J., van den Wijngaard, A.
Date: 2016
Source: European journal of human genetics : EJHG   24(12): 1783-1791 (Journal)
Registered Authors: Bakkers, Jeroen, Chocron, Sonja
Keywords: none
MeSH Terms:
  • Animals
  • Dextrocardia/diagnosis
  • Dextrocardia/genetics*
  • Female
  • Fetus/pathology
  • Gene Deletion*
  • Genetic Diseases, X-Linked/diagnosis
  • Genetic Diseases, X-Linked/genetics*
  • HeLa Cells
  • Heterotaxy Syndrome/diagnosis
  • Heterotaxy Syndrome/genetics*
  • Homeodomain Proteins/genetics*
  • Homeodomain Proteins/metabolism
  • Humans
  • Infant, Newborn
  • Male
  • Mutation, Missense*
  • Pregnancy
  • Protein Transport
  • Transcription Factors/genetics*
  • Transcription Factors/metabolism
  • Zebrafish
PubMed: 27406248 Full text @ Eur. J. Hum. Genet.
ABSTRACT
Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.
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