title: Mutations in the ABCA3 gene are associated with cataract-microcornea syndrome.
abstract: OBJECTIVE
  Cataract-microcornea syndrome (CCMC) is an autosomal dominant inherited disease characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although mutations of several genes have been shown to cause dominant CCMC, in many patients the causative gene has not yet been identified. Our aim was to identify the disease-associated gene in Chinese patients with CCMC.
  
  
  METHODS
  The CCMC patients from two unrelated Chinese families and 26 sporadic patients were enrolled. All the patients were screened by Sanger sequencing with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing.
  
  
  RESULTS
  By sequencing the whole exome of three patients in a Chinese four-generation dominant CCMC family (Family A), three heterozygous missense mutation (c.115C>G, c.277G>A, and c.4393G>A) were identified in ATP-binding cassette protein A3 (ABCA3). At highly conserved positions, changes (c.115C>G and c.4393G>A) were predicted to have functional impacts and completely cosegregated with the phenotype. We further confirmed our finding by identifying another heterozygous missense mutation, c.2408C>T, in ABCA3 in an additional dominant CCMC family (Family B), which also cosegregated with the phenotype. Moreover, four heterozygous mutations, two missense mutations (c.4253A>T, c.2069A>T) and two splice site mutations (c.4053+2T>C, c.2765-1G>T) were identified from the sporadic patients. The ABCA3 protein was expressed in human lens capsule, choroid-retinal pigment epithelium and retinal pigment epithelial cells.
  
  
  CONCLUSIONS
  Mutations in the human ABCA3 gene were associated with lethal respiratory distress. Our study showed, for the first time to our knowledge, that mutations in ABCA3 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder.
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Yunhai
authors.initials: Y
authors.lastname: Dai
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Shiying
authors.initials: S
authors.lastname: Sun
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: BGI Tianjin Corporation, Tianjin, China.
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Guan
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Hao
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Renhua
authors.initials: R
authors.lastname: Wu
authors.affiliation: State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, Shandong Province, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Xie
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D003316:Corneal Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D022821:RNA Splice Sites
keywords: ABCA3; cataract-microcornea syndrome; exome sequencing; heterozygous mutation