Gang Liu1, Dingyuan Ma1, Jian Cheng1, Jingjing Zhang1, Chunyu Luo1, Yun Sun1, Ping Hu1, Yuguo Wang1, Tao Jiang2, Zhengfeng Xu3. 1. State key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, No.123, Tianfeixiang, Mochou Road, Nanjing, 210004, Jiangsu Province, China. 2. State key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, No.123, Tianfeixiang, Mochou Road, Nanjing, 210004, Jiangsu Province, China. jiangzhang784@163.com. 3. State key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, No.123, Tianfeixiang, Mochou Road, Nanjing, 210004, Jiangsu Province, China. zhengfeng_xu_nj@163.com.
Abstract
BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder characterized by copper accumulation. ATP7B gene mutations lead to ATP7B protein dysfunction, which in turn causes Wilson's disease. CASE PRESENTATION: We describe a male case of Wilson's disease diagnosed at 10 years after routine biochemical test that showed low serum ceruloplasmin levels and Kayser-Fleischer rings in both corneas. Analysis of the ATP7B gene revealed compound heterozygous mutations in the proband, including the reported c.3517G > A mutation and a novel c.532_574del mutation. The c.532_574del mutation covered a 43-bp region in exon 2, and resulted in a frameshift mutation (p.Leu178PhefsX10). By base sequence analysis, two microhomologies (TCTCA) were observed on both deletion breakpoints in the ATP7B gene. Meanwhile, the presence of some sequence motifs associated with DNA breakage near the deletion region promoted DNA strand break. CONCLUSIONS: By comparison, a replication-based mechanism named fork stalling and template switching/ microhomology-mediated break-induced replication (FoSTeS/MMBIR) was used to explain the formation of this novel deletion mutation.
BACKGROUND:Wilson's disease (WD) is an autosomal recessive disorder characterized by copper accumulation. ATP7B gene mutations lead to ATP7Bprotein dysfunction, which in turn causes Wilson's disease. CASE PRESENTATION: We describe a male case of Wilson's disease diagnosed at 10 years after routine biochemical test that showed low serum ceruloplasmin levels and Kayser-Fleischer rings in both corneas. Analysis of the ATP7B gene revealed compound heterozygous mutations in the proband, including the reported c.3517G > A mutation and a novel c.532_574del mutation. The c.532_574del mutation covered a 43-bp region in exon 2, and resulted in a frameshift mutation (p.Leu178PhefsX10). By base sequence analysis, two microhomologies (TCTCA) were observed on both deletion breakpoints in the ATP7B gene. Meanwhile, the presence of some sequence motifs associated with DNA breakage near the deletion region promoted DNA strand break. CONCLUSIONS: By comparison, a replication-based mechanism named fork stalling and template switching/ microhomology-mediated break-induced replication (FoSTeS/MMBIR) was used to explain the formation of this novel deletion mutation.
Authors: Feng Zhang; Mehrdad Khajavi; Anne M Connolly; Charles F Towne; Sat Dev Batish; James R Lupski Journal: Nat Genet Date: 2009-06-21 Impact factor: 38.330