ZFIN ID: ZDB-PUB-150124-4
Genetic Heterogeneity of Pseudoxanthoma Elasticum: The Chinese Signature Profile of ABCC6 and ENPP1 Mutations
Jin, L., Jiang, Q., Wu, Z., Shao, C., Zhou, Y., Yang, L., Uitto, J., Wang, G.
Date: 2015
Source: The Journal of investigative dermatology   135(5): 1294-302 (Journal)
Registered Authors: Zhou, Yong
Keywords: none
MeSH Terms:
  • Adolescent
  • Adult
  • Alleles
  • Animals
  • Asian Continental Ancestry Group/genetics*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Computational Biology
  • Female
  • Frameshift Mutation/genetics
  • Genetic Heterogeneity*
  • Humans
  • Infant
  • Liver/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Multidrug Resistance-Associated Proteins/genetics*
  • Multidrug Resistance-Associated Proteins/metabolism
  • Mutation/genetics*
  • Mutation, Missense/genetics
  • Phosphoric Diester Hydrolases/genetics*
  • Pseudoxanthoma Elasticum/genetics*
  • Pyrophosphatases/genetics*
  • RNA, Messenger/genetics
  • Young Adult
  • Zebrafish
PubMed: 25615550 Full text @ J. Invest. Dermatol.
FIGURES
ABSTRACT
Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder characterized by ectopic mineralization, is caused by mutations in the ABCC6 gene. We examined clinically 29 Chinese PXE patients from unrelated families, so far the largest cohort of Asian PXE patients. In a subset of 22 patients, we sequenced ABCC6 and another candidate gene, ENPP1, followed by pathogenicity analyses for each variant. We identified a total of 17 distinct mutations in ABCC6, 15 of them being previously unreported, including 5 frame-shift and 10 missense variants. In addition, a missense mutation in combination with a recurrent nonsense mutation in ENPP1 was discovered in a pediatric PXE case. No cases with p.R1141X or del23-29 mutations, common in Caucasian patient populations, were identified. The 10 missense mutations in ABCC6 were expressed in mouse liver via hydrodynamic tail-vein injections. One mutant protein showed cytoplasmic accumulation indicating abnormal subcellular trafficking, while the other nine mutants showed correct plasma membrane location. These nine mutations were further investigated for their pathogenicity using a recently developed zebrafish mRNA rescue assay. Minimal rescue of the morpholino-induced phenotype was achieved with 8 of the 9 mutant human ABCC6 mRNAs tested, implying pathogenicity. This study demonstrates that the Chinese PXE population harbors unique ABCC6 mutations. These genetic data have implications for allele-specific therapy currently being developed for PXE.Journal of Investigative Dermatology accepted article preview online, 23 January 2015. doi:10.1038/jid.2015.10.
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