A frameshift mutation in the CHM gene causes choroideremia with acute angle‑closure glaucoma

Ouyang,Pingbo; Li,Yun; Zhang,Feng; Zhu,Chengzhang; Zou,Beiji; Le,Jianlan; Zhang,Lusi

doi:10.3892/mmr.2018.8851

A frameshift mutation in the CHM gene causes choroideremia with acute angle‑closure glaucoma

Authors:
- Pingbo Ouyang
- Yun Li
- Feng Zhang
- Chengzhang Zhu
- Beiji Zou
- Jianlan Le
- Lusi Zhang
View Affiliations

Affiliations: School of Information Science and Engineering, Central South University, Changsha, Hunan 410083, P.R. China, Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: April 5, 2018 https://doi.org/10.3892/mmr.2018.8851
Pages: 7918-7924

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Choroideremia is an X‑linked recessive chorioretinal degenerative disease that is characterized by progressive centripetal loss of the photoreceptor, retinal pigment epithelium (RPE), and choriocapillaris layers. The CHM gene [choroideremia (Rab escort protein 1)] has been identified as the pathogenic gene in choroideremia. The aim of the present study was to describe the clinical and genetic characteristics of a family with choroideremia family. In the present study, a family with choroideremia presenting with serious chorioretinal atrophy and pigment proliferation, shallow anterior chambers, angle closure and high intraocular pressure (IOP) were recruited. The affected family members underwent a complete ophthalmologic examination. DNA samples obtained from the proband II:1 and the patient II:2 were used for targeted exome sequencing of the CHM gene. PCR amplification and Sanger sequencing were used to validate the variations exhibited in family members and controls. A novel frameshift mutation c.280delA (p.Thr94LeufsTer32), in CHM was identified in the male proband, the normal carrier I:2 and the phenotyped carrier II:2, which was absent in the normal individual II:3 as well as in 200 normal controls. Comparing the amino acid sequences of CHM between multiple species through Clustal Omega indicated conserved amino acids in these mutant sites. Additionally, an X‑chromosome inactivation (XCI) assay was performed in the female carriers in the family, in which DNA of the abnormal carrier II:2 and normal carrier I:2 showed a random XCI pattern. To conclude, the present findings strongly indicate that the c.280delA mutation is a disease‑causing mutation in our choroideremia pedigree with acute angle‑closure glaucoma.

View Figures

View References

1	Coussa RG and Traboulsi EI: Choroideremia: A review of general findings and pathogenesis. Ophthalmic Genet. 33:57–65. 2012. View Article : Google Scholar : PubMed/NCBI
2	Rudolph G, Preising M, Kalpadakis P, Haritoglou C, Lang GE and Lorenz B: Phenotypic variability in three carriers from a family with choroideremia and a frameshift mutation 1388delCCinsG in the REP-1 gene. Ophthalmic Genet. 24:203–214. 2003. View Article : Google Scholar : PubMed/NCBI
3	Renner AB, Kellner U, Cropp E, Preising MN, MacDonald IM, van den Hurk JA, Cremers FP and Foerster MH: Choroideremia: Variability of clinical and electrophysiological characteristics and first report of a negative electroretinogram. Ophthalmology. 113:e1–e10. 2006. View Article : Google Scholar
4	van den Hurk JA, van de Pol DJ, Wissinger B, van Driel MA, Hoefsloot LH, de Wijs IJ, van den Born LI, Heckenlively JR, Brunner HG, Zrenner E, et al: Novel types of mutation in the choroideremia (CHM) gene: A full-length L1 insertion and an intronic mutation activating a cryptic exon. Hum Genet. 113:268–275. 2003. View Article : Google Scholar : PubMed/NCBI
5	Radziwon A, Arno G, Wheaton K D, McDonagh EM, Baple EL, Webb-Jones K, Birch G D, Webster AR and MacDonald IM: Single-base substitutions in the CHM promoter as a cause of choroideremia. Hum Mutat. 38:704–715. 2017. View Article : Google Scholar : PubMed/NCBI
6	Edwards TL, Williams J, Patrício MI, Simunovic MP, Shanks M, Clouston P and MacLaren RE: Novel non-contiguous exon duplication in choroideremia. Clin Genet. 93:144–148. 2018. View Article : Google Scholar : PubMed/NCBI
7	Leung KF, Baron R and Seabra MC: Thematic review series: Lipid posttranslational modifications. geranylgeranylation of Rab GTPases. J Lipid Res. 47:467–475. 2006. View Article : Google Scholar : PubMed/NCBI
8	Ali BR and Seabra MC: Targeting of Rab GTPases to cellular membranes. Biochem Soc Trans. 33:652–656. 2005. View Article : Google Scholar : PubMed/NCBI
9	Larijani B, Hume AN, Tarafder AK and Seabra MC: Multiple factors contribute to inefficient prenylation of Rab27a in Rab prenylation diseases. J Biol Chem. 278:46798–46804. 2003. View Article : Google Scholar : PubMed/NCBI
10	Futter CE, Ramalho JS, Jaissle GB, Seeliger MW and Seabra MC: The role of Rab27a in the regulation of melanosome distribution within retinal pigment epithelial cells. Mol Biol Cell. 15:2264–2275. 2004. View Article : Google Scholar : PubMed/NCBI
11	Seabra MC, Ho YK and Anant JS: Deficient geranylgeranylation of Ram/Rab27 in choroideremia. J Biol Chem. 270:24420–24427. 1995. View Article : Google Scholar : PubMed/NCBI
12	Tolmachova T, Anders R, Abrink M, Bugeon L, Dallman MJ, Futter CE, Ramalho JS, Tonagel F, Tanimoto N, Seeliger MW, et al: Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia. J Clin Invest. 116:386–394. 2006. View Article : Google Scholar : PubMed/NCBI
13	Tolmachova T, Wavre-Shapton ST, Barnard AR, MacLaren RE, Futter CE and Seabra MC: Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia. Invest Ophthalmol Vis Sci. 51:4913–4920. 2010. View Article : Google Scholar : PubMed/NCBI
14	Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM and Belmont JW: Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 51:1229–1239. 1992.PubMed/NCBI
15	Beever C, Lai BP, Baldry SE, Peñaherrera MS, Jiang R, Robinson WP and Brown CJ: Methylation of ZNF261 as an assay for determining X chromosome inactivation patterns. Am J Med Genet A. 120A:439–441. 2003. View Article : Google Scholar : PubMed/NCBI
16	Li S, Guan L, Fang S, Jiang H, Xiao X, Yang J, Wang P, Yin Y, Guo X, Wang J, et al: Exome sequencing reveals CHM mutations in six families with atypical choroideremia initially diagnosed as retinitis pigmentosa. Int J Mol Med. 34:573–577. 2014. View Article : Google Scholar : PubMed/NCBI
17	Renner AB, Fiebig BS, Cropp E, Weber BH and Kellner U: Progression of retinal pigment epithelial alterations during long-term follow-up in female carriers of choroideremia and report of a novel CHM mutation. Arch Ophthalmol. 127:907–912. 2009. View Article : Google Scholar : PubMed/NCBI
18	Zhou Q, Liu L, Xu F, Li H, Sergeev Y, Dong F, Jiang R, MacDonald I and Sui R: Genetic and phenotypic characteristics of three Mainland Chinese families with choroideremia. Mol Vis. 18:309–316. 2012.PubMed/NCBI
19	Perez-Cano HJ, Garnica-Hayashi RE and Zenteno JC: CHM gene molecular analysis and X-chromosome inactivation pattern determination in two families with choroideremia. Am J Med Genet A. 149A:2134–2140. 2009. View Article : Google Scholar : PubMed/NCBI
20	Esposito G, De Falco F, Tinto N, Testa F, Vitagliano L, Tandurella IC, Iannone L, Rossi S, Rinaldi E, Simonelli F, et al: Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase. Hum Mutat. 32:1460–1469. 2011. View Article : Google Scholar : PubMed/NCBI
21	Baron RA and Seabra MC: Rab geranylgeranylation occurs preferentially via the pre-formed REP-RGGT complex and is regulated by geranylgeranyl pyrophosphate. Biochem J. 415:67–75. 2008. View Article : Google Scholar : PubMed/NCBI