Sequence CLCN1 and SCN4A in patients with Nondystrophic myotonias in Chinese populations: Genetic and pedigree analysis of 10 families and review of the literature

Abstract

Myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonias(SCM) were belonged to Non-dystrophic myotonias, in which muscle relaxation is delayed after voluntary or evoked contraction. These diseases can not be simply distinguished only based on symptoms and signs but also on genetics: more than 100 mutations in the CLCN1 gene have been associated with MC, while at least 20 mutations in the SCN4A gene have been associated with PC and SCM. Most of these genetics studies have been conducted outside China, only several MC, PC, and SCM families accepted gene scan were reported in China. Therefore we analyzed genetic mutations in CLCN1 and SCN4A in 10 Chinese families clinically diagnosed with Non-dystrophic myotonias. Our result revealed 12 potential disease-causing mutations(3 mutations were novel) that were present in the probands and affected family members. We also reviewed all available literature on mutations linked to these 3 disease in Chinese populations. Our results may help identify genetic determinants as well as clarify genotype-phenotype relationships.

Keywords: CLCN1; SCN4A; myotonia congenita; paramyotonia congenita; sodium channel myotonias.

Figure 1.

Sequencing chromatograms of mutations in CLCN1(Family 1–5) and related pedigrees of families with MC. Black arrows indicate mutations; dark squares, affected patients; arrows, the proband. (A) Sequencing chromatogram of the c.871G > A(p.E291K) mutation in CLCN1 and the pedigree of family 1. The black arrow shows the position of a G-to-A transition at nucleotide 871 that replaces Glu with Lys at codon 291. The proband and his Father suffered from MC. (B) Sequencing chromatogram of the c.1013G > A(p.R338Q) and c.139C > T(p.R47W) mutation in CLCN1 and the pedigree of family 2. The first black arrow shows the position of a G-to-A transition at nucleotide 1013 that replaces Arg with Gln at codon 338. The second black arrow shows the position of a C-to-T transition at nucleotide 139 that replaces Arg with Trp at codon 47. The proband suffered from MC. (C) Sequencing chromatogram of the c.892G > A(p.A298T) mutation in CLCN1 and the pedigree of families 3 and 4. The black arrow shows the position of a G-to-A transition at nucleotide 892 that replaces Ala with Thr at codon 298. In both families, the proband's father and grandfather suffered from MC. (D) Sequencing chromatogram of the c.350A > G(p.D117G) mutation in CLCN1 and the pedigree of family 5. The black arrow shows the position of an A-to-G transition at nucleotide 350 that replaces Asp with Gly at codon 117. The proband's mother suffered from MC.

Figure 2.

Sequencing chromatograms of SCN4A mutation and related pedigrees of SCM(Family 6–7) and PC(Family 8–10) families in which the mutations are present. Black arrows indicate mutations; dark squares, affected patients; arrows, the proband. (A) Sequencing chromatogram of the c.1333G > A(p.V445M) mutation in SCN4A and pedigree of family 6. The black arrow shows the position of an G-to-A transition at nucleotide 1333 that leads to the replacement of Val by Met at codon 117. The proband, his brother and Mother suffered from SCM. (B) Sequencing chromatogram of the c.3917G > T(p.G1306V) mutation at SCN4A gene and the pedigree of Family 7 who carried the p.G1306V mutation. The arrow shows the position of an G-to-T transition at nucleotide 3917 that leads to the replacement of Gly by Val at codon 1306. The proband, his Father and Grandfather suffered from SCM. (C) Sequencing chromatogram of the c.4343G > A(p.R1448H) mutation at SCN4A gene and pedigree of family 8. The black arrow shows the position of a G-to-A transition at nucleotide 4343 that leads to the replacement of Arg by His at codon 1448. The proband and his Father suffered from PC. (D) Sequencing chromatogram of the c.3938C > T(p.T1313M) mutationat SCN4A gene and the pedigree of Family 9. The arrow shows the position of an C-to-T transition at nucleotide 3938 at SCN4A gene that leads to the replacement of Thr by Met at codon 1313. The proband, his Mother and Grandfather suffered from PC. (E) Sequencing chromatogram of the c.2638_2640delAAG(E879del) mutation at SCN4A gene Family 10. The arrow shows the position AAG was deleted and leads to the deletion of Lys at codon 879. The proband and his Mother suffered from PC.

Figure 3.

Presentation of (A) all mutations in CLCN1 reported in Chinese patients with MC in the present study and in the literature, and (B) all mutations in SCN4A reported in Chinese patients with SCM or PC in the present study and in the literature.