Mutation and Phenotype Analysis in Patients with Osteopetrosis Caused by Loss-of-Function Mutation of CLCN7 Single Allele
1. Department of Endocrinology and Metabolism, Foresea Insurance Guangzhou General Hospital, Guangzhou 511300, China
2. Department of Endocrinology, the Second People’s Hospital of Guangdong Province, Guangzhou 510220, China
| Abstract: | Objective: To investigate the relationship between gene mutation and clinical phenotype in patients with autosomal dominant osteopetrosis type 2 (ADO2) caused by single allele mutation of CLCN7. Methods: The two ADO2 cases were clinically described in detail, CLCN7 gene were screened by the next generation sequence assay, and validated by Sanger method. The hazard of mutations was evaluated on PolyPhen2 website. Literature review helped to browse and gather ADO2 cases with CLCN7 data, accordingly all found CLCN7 mutant loci were mapped on the peptide chain, and clinical presentations in each case were tentatively summarized corresponding gene mutation. Phenotype was classified as mild type, intermediate type and severe type according to the degree of clinical presentation. Mild type presents mainly with bone and/or joint pain and occasional bone fracture, intermediate type with additional multiple and recurrent bone fracture, sever type with hematopoietic dysfunction in addition to recurrent bone fractures. Results: The first case was a 30 year old man presenting as mild ADO2 with shorter stature than familial hereditary height, as well as back pain and knee joint pain for up-to nine years. The second case was a 13 year old boy who suffered from recurrent bone fractures since four years ago in addition to short stature and more severe bone pain, but had normal peripheral blood picture. His prominent bone change showed by X-Ray indicated a more typical and severe osteopetrosis than the former. Gene analysis indicated a mutation of c.2284C>T (E24), p.R762W in the first case and c.856C>T (E10), p.R286W in the second case. Literature review gathered 42 pathogenic mutations, mild, intermediate and severe clinical type account for 33.3%, 46.7% and 20.0%, respectively. Among family members of probands, 58.8% had unaffected mutation-carrier, and 44.7% had family history of the disease. Conclusions: In spite of single allele inactivation, CLCN7 related ADO2 may cause highly various clinical phenotype of osteopetrosis, covering normal unaffected, mild, intermediate and severe conditions. The relationship between genotype and phenotype remains obscure in the disease. |
| Keywords: | CLCN7 Gene; Autosomal Dominant Osteopetrosis; Gene Mutation; Genotype and Phenotype; Mutation Detection |
| DOI: | 10.57237/j.wjcm.2022.01.005 |
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Received: 6 September 2022
Accepted: 17 October 2022
Published Online: 15 December 2022
Funding
| 1. | 广东省医学科学技术研究基金资助 (A2021005). |
References
| [1] | Stark Z and Savarirayan R. Osteopetrosis. Orphanet Journal of Rare Diseases [J], 2009, 4:5. DOI: 10.1186/1750-1172-4-5. |
| [2] | Sobacchi C, Schulz A, Coxon FP, et al. Osteopetrosis: genetics, treatment and new insights into osteoclast function [J]. Nat Rev Endocrinol, 2013, 9: 522–536, DOI: 10.1038/nrendo.2013.137. |
| [3] | Sobacchi C, Villa A, Schulz A, et al. CLCN7-Related osteopetrosis. GeneReviews® [Internet]. Initial Posting: February 12, 2007; Last Update: June 9, 2016. https://www.ncbi. nlm.nih.gov/ books/NBK1127/ |
| [4] | Waguespack SG, Hui SL, DiMeglio LA, et al. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation [J]. J Clin Endocrinol Metab, 2007, 92(3): 771–778. |
| [5] | 金文胜, 郭燕燕,李红梅, 等. 两个新的分别来自父母的SLC26A4的突变导致复合杂合突变型甲状腺耳聋综合症[J].中国医师杂志, 2017, 19 (6): 919-921. DOI: 10.3760/cma.j.issn.1008-1372.2017.06.036. |
| [6] | 金文胜, 郭燕燕, 宋丹丹, 等. 一个新的AVPR2基因缺失-框移突变所致的X连锁肾性尿崩症家系 [J]. 中华内分泌代谢杂志, 2017, 33 (7): 602-604. DOI: 3760/ cma.j.issn.1000-6699.2017.07.013. |
| [7] | Zheng LC, Ou Yang XL, Liu GC, et al. 99Tcm-MDP imaging of osteopetrosis case report [J]. Medicine, 2015, 94 (22): e929. DOI: 10.1097/MD.0000000000000929 |
| [8] | Kormak U, Kasper D, Bosl MR, et al. Loss of the ClC-7 chloride channel Leads to osteopetrosis in mice and man [J]. Cell, 2001, 104, 205–215. |
| [9] | Piret SE, Gorvin CM, Trinh A,et al. Autosomal dominant osteopetrosis associated with renal tubular acidosis is due to a CLCN7 mutation [J]. Am J Med Genet A, 2016, 170 (11): 2988-2992. DOI: 10.1002/ajmg.a.37755. |
| [10] | Mackie EJ, Ahmed YA, Tatarczuch L, et al. Endochondral ossification: how cartilage is converted into bone in the developing skeleton [J]. Int J Biochem Cell Biol, 2008, 40 (1): 46-62. DOI: 10.1016/j.biocel.2007.06.009. |
| [11] | Thomas J. Jentsch. Discovery of CLC transport proteins: cloning, structure, function and pathophysiology [J]. J Physiol, 2015, 593 (18): 4091–4109. DOI: 10.1113/JP270043. |
| [12] | Whyte MP, Kempa LG, McAlister WH, et al. Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schnberg disease (chloride channel 7 deficiency osteopetrosis) among the sclerosing bone disorders [J]. Journal of Bone and Mineral Research, 2010, 25 (11): 2515–2526. DOI: 10.1002/jbmr.130. |
| [13] | Veitia RA. Exploring the molecular etiology of dominant-negative mutations [J]. Plant Cell, 2007, 19 (12): 3843–3851.DOI: 10.1105/tpc.107.055053 |
| [14] | Seidman JG and Seidman C. Transcription factor haploinsufficiency: when half a loaf is not enough [J]. J Clin Invest, 2002, 109 (4): 451–455. DOI: 10.1172/JCI15043. |
| [15] | 曾好, 蒋丹华, 陈明晖,等. 三个石骨症致病基因内的新突变及其基因型-表型 [J]. 中山大学学报（医学科学版）, 2016, 37 (5): 657-665. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2016.0316 |
| [16] | Cleiren E, Bénichou O, Van Hul E, et al. Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene [J]. Hum Mol Genet, 2001, 10 (25): 2861-2867. |
| [17] | Pangrazio A, Pusch M, Caldana E, et al. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations [J]. Hum Mutat, 2010, 31 (1): E1071-80. DOI: 10.1002/humu.21167.19 |
| [18] | Wang C, Zhang H, He JW, et al. The virulence gene and clinical phenotypes of osteopetrosis in the Chinese population: six novel mutations of the CLCN7 gene in twelve osteopetrosis families [J]. J Bone Miner Metab, 2012, 30 (3): 338-348. DOI: 10.1007/s00774-011-0319-z. |
| [19] | Pang Q, Chi Y, Zhao Z, et al. Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients [J]. Osteoporos Int, 2016, 27 (3): 1047-1055. DOI: 10.1007/s00198-015-3320-x. |
| [20] | Xue Y, Wang W, Mao T, et al. Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia [J]. J Craniomaxillofac Surg, 2012, 40(5): 416-20.DOI: 10.1016/j.jcms.2011.07.014. |
| [21] | Waguespack SG, Koller DL, White KE, et al. Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II [J]. J Bone Miner Res, 2003, 18(8):1513-1518. |
| [22] | Zheng H, Zhang Z, He JW, et al. Identification of two novel CLCN7 gene mutations in three Chinese families with autosomal dominant osteopetrosis type II [J]. Joint Bone Spine, 2014, 81 (2): 188-189. DOI: 10.1016/j.jbspin.2013.06.014. |
| [23] | Zheng H, Shao C, Zheng Y, et al. Two novel mutations of CLCN7 gene in Chinese families with autosomal dominant osteopetrosis (type II) [J]. J Bone Miner Metab, 2016, 34 (4): 440-446. DOI: 10.1007/s00774-015-0682-2. |
| [24] | Frattini A, Pangrazio A, Susani L, et al. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis [J]. J Bone Miner Res, 2003, 18 (10): 1740-7. DOI:10.1359/jbmr.2003.18.10.1740 |
| [25] | Deng H, He D, Rong P, et al. Novel CLCN7 mutation identified in a Han Chinese family with autosomal dominant osteopetrosis-2 [J]. Mol Pain, 2016, 12:1-7. DOI: 10.1177/ 1744806916652628. |
| [26] | 赵万民, 段小红. 骨硬化症患者CLCN7基因突变的生物信息学分析 [J]. 口腔生物医学, 2017, 8 (1): 1-6. DOI: 10.3969/j.issn.1674-8603.2017.01.001. |
| [27] | Rashid BM, Rashid NG, Schulz A, et al. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series [J]. J Med Case Rep, 2013, 7:7. DOI: 10.1186/1752-1947-7-7. |
| [28] | 宋玉文, 徐晓杰, 吕芳, 等. CLCN7基因突变致常染色体显性遗传骨硬化症: 1例家系研究 [J]. 中华骨质疏松和骨矿盐疾病杂志. 2017, 10 (4): 328-335. |
| [29] | Chen X, Zhang K, Hock J, et al. Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C4T mutation in CLCN7 [J]. Bone Research, 2016, 4: 16035. DOI: 10.1038/boneres.2016.35. |
| [30] | Campos-Xavier AB, Casanova JL, Doumaz Y, et al. Intrafamilial phenotypic variability of osteopetrosis due to chloride channel 7 (CLCN7) mutations [J]. Am J Med Genet A, 2005, 133A (2): 216-8. DOI: 10.1002/ajmg.a.3049025. |
| [31] | 李晓刚, 苏楠, 李灿, 等. 一例Ⅱ型常染色体显性骨硬化症患者氯离子蛋白通道7基因突变分析 [J]. 中华医学遗传学杂志. 2014, 31 (5): 612-614. |
| [32] | Letizia C, Taranta A, Migliaccio S, et al. Type II benign osteopetrosis (Albers-Schönberg disease) caused by a novel mutation in CLCN7 presenting with unusual clinical manifestations [J]. Calcif Tissue Int, 2004, 74 (1): 42-6. DOI: 10.1007/s00223-002-1087-5. |
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