Myotonia congenita: novel mutations in CLCN1 gene

Figures & data

Table 1. Detailed clinical features of subjects with CLCN1 mutation

Patients	Patient T1	Patient T2	Patient T3	Patient T4	Patient T5
Sex	Female	Male	Male	Male	Male
Age at examination(yr)	19	27	16	27	34
Age at onset(yr)	4	2	4	1	9
Family history	+	+	−	+	+
Inheritance	AD	AD	AR	AR	AR
Symptom at onset	LL stiffness	Lid myotonia	LL stiffness	LL stiffness	LL stiffness
Clinical myotonia
Lids	−	+	+	+	−
Tongue	−	+	+	+	−
Jaw muscles	−	+	+	+	−
Neck muscles	−	+	−	+	−
Hands	+	+	+	+	+
Legs	+	+	+	+	+
Warm-up	+	+	+	+	+
Grip myotonia	+	+	+	+	+
Triggers
Cold	−	+	+	+	+
Stress	+	+	+	+	−
Hunger	+	+	+	−	−
Fatigue	+	+	+	+	−
Excise	+	+	+	+	+
Others
Muscle hypertrophy	+	+	+	+	+
Muscle pain	−	−	+	−	−
Transient weakness	+	−	−	+	−
Permanent weakness	−	−	−	−	−
Electromyography	Myotonic discharges	Myotonic discharges	Myotonic discharges	Myotonic discharges	Myotonic discharges
Mutation in CLCN1	p.Y261C; p.G859D	p.G523D	p.M560T	p.M560T; IVS19 + 2T > C	p.R47W; p.V229M
Diagnosis	Thomsen disease	Thomsen disease	Becker disease	Becker disease	Becker disease

Note: yr, years; LL, lower limb; AR, autosomal recessive; AD, autosomal dominant.

Figure 1. Pedigree and mutational analysis of CLCN1 in myotonia congenita patients. (A) Family 1: The c.782A > G mutation in exon 7 and c.2576G > A mutation in exon 22, both mutations were shown in the Patient T1 (III:1), her affected aunt (II:3) and her asymptomatic father (II:1). (B) Family 2: The c.1568G>A mutation in exon 14, and this mutation was identified in his affected mother (II:1), uncle (II:3), aunt (II:4) and grandmother (I:2). (C) Family 3: The homozygous c.1679T > C mutation in exon 15 was found in the proband (V:1) and from his heterozygous parents who were relatives. (D) Family 4: The c.1679T>C mutation in exon 15 and c.2364 + 2T > C mutation in intron 19, inherited from his father (I:1) and mother (I:2) respectively, were found in the proband (II:3) and his 2 sisters (II:1, II:2). (E) Family 5: The paternal (I:1) c.139C > T mutation in exon 1 and maternal (I:2) c.685G > A mutation in exon5, were found in the proband (II:1) and his sister (II:2).

Figure 2. Localization on the human skeletal muscle chloride channel of the 7 mutations detected in this study.

Table 2. Mutations of CLCN1 identified in the study

Patients	Nucleotide substitution	Change in protein	Change in codon	Domain	Exon /intron	Mode of inheritance	Hom/Het	Probability
Patient T1	c.782A > G	p.Y261C	TAC→TGC	F-G linking	Exon7	AD	Het	0.9996
	c.2576G > A	p.G859D	GGC→GAC	C-terminal	Exon22		Het	0.9999
Patient T2	c.1568G > A	p.G523D	GGC→GAC	O	Exon14	AD	Het	0.9999
Patient T3	c.1679T > C	p.M560T	ATG→ACG	Q	Exon15	AR	Hom	0.9999
Patient T4	c.1679T > C	p.M560T	ATG→ACG	Q	Exon15	AR	Het	0.9999
	IVS19 + 2T > C (c.2364 + 2T > C)	—	—	—	Intron19		Het	1
Patient T5	c.139C > T	p.R47W	CGG→TGG	N terminal	Exon1	AR	Het	0.9999
	c.685G > A	p.V229M	GTG→ATG	E-F linking	Exon5		Het	0.9914

Note: AR, autosomal recessive; AD, autosomal dominant.