title: A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient.
abstract: Osteopetrosis is a group of heterogeneous disorders caused by the dysfunction of osteoclasts. The CLCN7 and TCIRG1 genes are the major obligate genes responsible for infantile malignant osteopetrosis (IMO). IMO patients usually die in infancy or before three years of age. In this study, we report a patient who was diagnosed with IMO at seven months of age. The patient presented with classical radiological features of IMO. She also exhibited erythropenia, thrombocytopenia, hepatosplenomegaly and neurodegeneration. The parents discontinued any medical treatment for the patient. Surprisingly, the patient's condition did not deteriorate when she was admitted a second time at the age of four years and nine months, despite not receiving any medical support during the untreated period. We sequenced the CLCN7 and TCIRG1 genes of the patient and her parents and identified a novel c.285+1G>A (IVS3+1G>A) mutation and the known c.896C>T (p.Ala299Val) mutation. The novel c.285+1G>A mutation occurred on the splice donor of the third intron of CLCN7. This mutation was predicted to interfere with normal splicing between exons 3 and 4, thereby truncating 711 amino acids from the C terminus and resulting in the loss of all of the functional domains of the encoded protein. The c.896C>T (p.Ala299Val) mutation was a previously known pathogenic mutation. We did not find any pathogenic mutations in the TCIRG1 gene. CLCN7-related osteopetrosis is known to have a high phenotype heterogeneity. Our study demonstrates a wide heterogeneity in the progression of the phenotypes and expanded the mutational spectrum for the CLCN7 gene.
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine and Center for Genome Research, Sun Yat-sen University, Guangzhou, China.
authors.forename: Binghui
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Department of Radiology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Radiology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine and Center for Genome Research, Sun Yat-sen University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine and Center for Genome Research, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Neurology, the First Affiliated Hospital of SunYat-sen University, Guangzhou, China.
authors.forename: Huijiao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Reproductive Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.affiliation: Xinhua College, Sun Yat-sen University, Guangzhou, China; Beijing Genomics Institute (BGI) in Shenzhen, China. Electronic address: ywzhong@hotmail.com.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D018118:Chloride Channels / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010022:Osteopetrosis / Q000151:congenital* / Q000000981:diagnostic imaging* / Q000235:genetics*; D022821:RNA Splice Sites; D011859:Radiography; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels; D022821:RNA Splice Sites; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: CLCN7; Mutation; Osteopetrosis