title: Genetic heterogeneity of pseudoxanthoma elasticum: the Chinese signature profile of ABCC6 and ENPP1 mutations.
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, and conducted pathogenicity analyses for each variant. We identified a total of 17 distinct mutations in ABCC6, 15 of them being, to our knowledge, previously unreported, including 5 frameshift 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 the 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 eight of the nine 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.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Qiujie
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Changxia
authors.initials: C
authors.lastname: Shao
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Dermatology, PLA General Hospital, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Luting
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address: Jouni.Uitto@jefferson.edu.
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: xjwgang@fmmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D044466:Asian People / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019295:Computational Biology; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult; D015027:Zebrafish
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D012333:RNA, Messenger; C102029:ABCC6 protein, human; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1