A Chinese pedigree with a novel mutation in GJB1 gene and a rare variation in DHTKD1 gene for diverse Charcot‑Marie‑Tooth diseases

Zhao,Zhen‑Hua; Chen,Zhi‑Ting; Zhou,Rui‑Ling; Wang,Yin‑Zhou

doi:10.3892/mmr.2019.10058

A Chinese pedigree with a novel mutation in GJB1 gene and a rare variation in DHTKD1 gene for diverse Charcot‑Marie‑Tooth diseases

Authors:
- Zhen‑Hua Zhao
- Zhi‑Ting Chen
- Rui‑Ling Zhou
- Yin‑Zhou Wang
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Affiliations: Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China, Department of Neurology, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
Published online on: March 19, 2019 https://doi.org/10.3892/mmr.2019.10058
Pages: 4484-4490

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Abstract

Charcot‑Marie‑Tooth (CMT) disease is a group of motor and sensory neuropathies with a high degree of pathological and genetic heterogenicity. The present study described 2 patients with CMT in a Chinese Han pedigree. The proband exhibited the classic manifestation of CMT with slowly progressing muscular atrophy and weakness. Electrophysiological examination highlighted axonal and demyelinating features. His mother did not have any symptoms, but did exhibit abnormal electrophysiological results. Next‑generation sequencing technology was employed to screen mutations in the genes associated with inherited motor never diseases. A novel mutation, c.528_530delAGT, in the gap junction protein beta 1 (GJB1) gene for CMTX, and a rare variation, c.2369C>T, in the dehydrogenase E1 and transketolase domain containing 1 (DHTKD1) gene for CMT disease type 2Q (CMT2Q), were identified in the proband and his mother. The results were verified by Sanger sequencing. Although the in silico analysis predicted no change in the 3‑dimensional structure, the clinical and electrophysiological presentation in the pedigree and the high evolutionary conservation of the affected amino acid supported the hypothesis that the c.528_530delAGT mutation in the GJB1 gene may be pathogenic in this pedigree. In silico analysis and high evolutionary conservation suggested the pathogenicity of the c.2369C>T mutation in the DHTKD1 gene; however, the clinical and electrophysiological performances of the proband and his mother did not conform to those of CMT2Q caused by the DHTKD1 gene. The present study provided additional information concerning the range of mutations of the GJB1 gene, which facilitated the understanding of the genotype‑phenotype association of CMT.

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1	Kazamel M and Boes CJ: Charcot marie tooth disease (CMT): Historical perspectives and evolution. J Neurol. 262:801–805. 2015. View Article : Google Scholar : PubMed/NCBI
2	Timmerman V, Strickland AV and Zuchner S: Genetics of Charcot-Marie-Tooth (CMT) disease within the frame of the human genome project success. Genes (Basel). 5:13–32. 2014. View Article : Google Scholar : PubMed/NCBI
3	Ionasescu VV, Ionasescu R and Searby C: Screening of dominantly inherited Charcot-Marie-Tooth neuropathies. Muscle Nerve. 16:1232–1238. 1993. View Article : Google Scholar : PubMed/NCBI
4	Bennett MV, Barrio LC, Bargiello TA, Spray DC, Hertzberg E and Sáez JC: Gap junctions: New tools, new answers, new questions. Neuron. 6:305–320. 1991. View Article : Google Scholar : PubMed/NCBI
5	Li H and Durbin R: Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 25:1754–1760. 2009. View Article : Google Scholar : PubMed/NCBI
6	Li R, Li Y, Fang X, Yang H and Wang J, Kristiansen K and Wang J: SNP detection for massively parallel whole-genome resequencing. Genome Res. 19:1124–1132. 2009. View Article : Google Scholar : PubMed/NCBI
7	McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M and DePristo MA: The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20:1297–1303. 2010. View Article : Google Scholar : PubMed/NCBI
8	Schwarz JM, Cooper DN, Schuelke M and Seelow D: MutationTaster2: Mutation prediction for the deep-sequencing age. Nat Methods. 11:361–362. 2014. View Article : Google Scholar : PubMed/NCBI
9	Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, et al: SWISS-MODEL: Homology modelling of protein structures and complexes. Nucleic Acids Res. 46:W1. W296–W303. 2018. View Article : Google Scholar : PubMed/NCBI
10	Bienert S, Waterhouse A, de Beer TA, Tauriello G, Studer G, Bordoli L and Schwede T: The SWISS-MODEL Repository-new features and functionality. Nucleic Acids Res. 45(D1): D313–D319. 2017. View Article : Google Scholar : PubMed/NCBI
11	Guex N, Peitsch MC and Schwede T: Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: A historical perspective. Electrophoresis. 30 (Suppl 1):S162–S173. 2009. View Article : Google Scholar : PubMed/NCBI
12	Benkert P, Biasini M and Schwede T: Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics. 27:343–350. 2011. View Article : Google Scholar : PubMed/NCBI
13	Bertoni M, Kiefer F, Biasini M, Bordoli L and Schwede T: Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology. Sci Rep. 7:104802017. View Article : Google Scholar : PubMed/NCBI
14	Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, Li J, Lewis RA and Reilly M: Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology. 64:1209–1214. 2005. View Article : Google Scholar : PubMed/NCBI
15	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 17:405–424. 2015. View Article : Google Scholar : PubMed/NCBI
16	Yuan JH, Sakiyama Y, Hashiguchi A, Ando M, Okamoto Y, Yoshimura A, Higuchi Y and Takashima H: Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1. Eur J Neurol. 25:1454–1461. 2018. View Article : Google Scholar : PubMed/NCBI
17	Wang Y and Yin F: A review of X-linked Charcot-Marie-Tooth disease. J Child Neurol. 31:761–772. 2016. View Article : Google Scholar : PubMed/NCBI
18	Scherer SS, Xu YT, Nelles E, Fischbeck K, Willecke K and Bone LJ: Connexin32-null mice develop demyelinating peripheral neuropathy. Glia. 24:8–20. 1998. View Article : Google Scholar : PubMed/NCBI
19	Hahn AF, Brown WF, Koopman WJ and Feasby TE: X-linked dominant hereditary motor and sensory neuropathy. Brain. 113:1511–1525. 1990. View Article : Google Scholar : PubMed/NCBI
20	Williams MM, Tyfield LA, Jardine P, Lunt PW, Stevens DL and Turnpenny PD: HMSN and HNPP. Laboratory service provision in the south west of England-two years' experience. Ann N Y Acad Sci. 883:500–503. 1999. View Article : Google Scholar
21	Ikegami T, Lin C, Kato M, Itoh A, Nonaka I, Kurimura M, Hirayabashi H, Shinohara Y, Mochizuki A and Hayasaka K: Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1. Am J Med Genet. 80:352–355. 1998. View Article : Google Scholar : PubMed/NCBI
22	Deschênes SM, Walcott JL, Wexler TL, Scherer SS and Fischbeck KH: Altered trafficking of mutant connexin32. J Neurosci. 17:9077–9084. 1997. View Article : Google Scholar : PubMed/NCBI
23	Kleopa KA, Yum SW and Scherer SS: Cellular mechanisms of connexin32 mutations associated with CNS manifestations. J Neurosci Res. 68:522–534. 2002. View Article : Google Scholar : PubMed/NCBI
24	Yum SW, Kleopa KA, Shumas S and Scherer SS: Diverse trafficking abnormalities of connexin32 mutants causing CMTX. Neurobiol Dis. 11:43–52. 2002. View Article : Google Scholar : PubMed/NCBI
25	VanSlyke JK, Deschenes SM and Musil LS: Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. Mol Biol Cell. 11:1933–1946. 2000. View Article : Google Scholar : PubMed/NCBI
26	Oh S, Ri Y, Bennett MV, Trexler EB, Verselis VK and Bargiello TA: Changes in permeability caused by connexin 32 mutations underlie X-linked Charcot-Marie-Tooth disease. Neuron. 19:927–938. 1997. View Article : Google Scholar : PubMed/NCBI
27	Nakagawa S, Maeda S and Tsukihara T: Structural and functional studies of gap junction channels. Curr Opin Struct Biol. 20:423–430. 2010. View Article : Google Scholar : PubMed/NCBI
28	Nualart-Marti A, Solsona C and Fields RD: Gap junction communication in myelinating glia. Biochim Biophys Acta. 1828:69–78. 2013. View Article : Google Scholar : PubMed/NCBI
29	Bortolozzi M: What's the function of connexin 32 in the peripheral nervous system? Front Mol Neurosci. 11:2272018. View Article : Google Scholar : PubMed/NCBI
30	Wang HL, Chang WT, Yeh TH, Wu T, Chen MS and Wu CY: Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiol Dis. 15:361–370. 2004. View Article : Google Scholar : PubMed/NCBI
31	Castro C, Gómez-Hernandez JM, Silander K and Barrio LC: Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations. J Neurosci. 19:3752–3760. 1999. View Article : Google Scholar : PubMed/NCBI
32	Abrams CK, Islam M, Mahmoud R, Kwon T, Bargiello TA and Freidin MM: Functional requirement for a highly conserved charged residue at position 75 in the gap junction protein connexin 32. J Biol Chem. 288:3609–3619. 2013. View Article : Google Scholar : PubMed/NCBI
33	Shy ME, Siskind C, Swan ER, Krajewski KM, Doherty T, Fuerst DR, Ainsworth PJ, Lewis RA, Scherer SS and Hahn AF: CMT1X phenotypes represent loss of GJB1 gene function. Neurology. 68:849–855. 2007. View Article : Google Scholar : PubMed/NCBI
34	Panosyan FB, Laura M, Rossor AM, Pisciotta C, Piscosquito G, Burns J, Li J, Yum SW, Lewis RA, Day J, et al: Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1). Neurology. 89:927–935. 2017. View Article : Google Scholar : PubMed/NCBI
35	Xu WY, Gu MM, Sun LH, Guo WT, Zhu HB, Ma JF, Yuan WT, Kuang Y, Ji BJ, Wu XL, et al: A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree. Am J Hum Genet. 91:1088–1094. 2012. View Article : Google Scholar : PubMed/NCBI
36	Hagen J, te Brinke H, Wanders RJ, Knegt AC, Oussoren E, Hoogeboom AJ, Ruijter GJ, Becker D, Schwab KO, Franke I, et al: Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria. J Inherit Metab Dis. 38:873–879. 2015. View Article : Google Scholar : PubMed/NCBI