Heterozygote manifestation in recessive generalized myotonia

Becker, P. E.

doi:10.1007/bf00273316

Cited by 23 publications

(11 citation statements)

References 3 publications

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“…Evidence for subclinical organ dysfunction is not uncommon among recessively inherited conditions, including some channelopathies. For example, in the skeletal muscle disorder recessive generalized myotonia, latent myotonia may be evident on electromyography in carriers of recessive chloride channel mutations (38). Interestingly, two mutations segregating as recessive alleles in our families have been identified previously in association with dominant syndromes (delF1617 in LQTS; G1408R in Brugada syndrome with conduction system disease) (19,21).…”

Section: Discussionmentioning

confidence: 57%

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Benson¹,

Wang²,

Dyment³

et al. 2003

J. Clin. Invest.

461

117

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Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the α subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel

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Section: Discussionmentioning

confidence: 57%

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Benson¹,

Wang²,

Dyment³

et al. 2003

J. Clin. Invest.

461

117

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“…In individuals heterozygous for recessive myotonia (GM), chloride conductance levels are expected to be 50 % of normal without having functional consequences. However, there are reports that some GM heterozygotes also present with mild symptoms (Becker, 1979;Zellweger et al, 1980;Streib and Sun, 1982). On the other hand, reducing chloride conductance to -25% using chloride channel inhibitors leads to myotonic symptoms in vitro (Kwiecinski et al, 1988 (Hanke and Miller, 1983;Bauer et al, 1991).…”

Section: Identification Of Missense Mutations In Thomsen's Diseasementioning

confidence: 99%

Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen).

et al. 1994

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Voltage‐gated ClC chloride channels play important roles in cell volume regulation, control of muscle excitability, and probably transepithelial transport. ClC channels can be functionally expressed without other subunits, but it is unknown whether they function as monomers. We now exploit the properties of human mutations in the muscle chloride channel, ClC‐1, to explore its multimeric structure. This is based on analysis of the dominant negative effects of ClC‐1 mutations causing myotonia congenita (MC, Thomsen's disease), including a newly identified mutation (P480L) in Thomsen's own family. In a co‐expression assay, Thomsen's mutation dramatically inhibits normal ClC‐1 function. A mutation found in Canadian MC families (G230E) has a less pronounced dominant negative effect, which can be explained by functional WT/G230E heterooligomeric channels with altered kinetics and selectivity. Analysis of both mutants shows independently that ClC‐1 functions as a homooligomer with most likely four subunits.

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“…Myotonia increased in severity until, two years later, myotonic signs were generalized, and the EMG showed myotonic discharges. Family studies failed to reveal any positive results; Becker (1979) year-old male who developed myotonia, especially of the hands, under treatment with propranolol, a p-blocker. There was EMG-evidence of myotonia in the right triceps muscle of a clinically healthy, 30year-old brother.…”

Section: Homocystinuriamentioning

confidence: 99%

Clinical consequences of heterozygosity for autosomal‐recessive diseases*,**

Vogel

1984

Clinical Genetics

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Heterozygotes of autosomal‐recessive diseases can often be recognized by special heterozygote tests, since enzyme activities are normally reduced in comparison with the normal homozygote state. In Drosophila, the majority of recessive lethal mutations shows a reduction of fitness in heterozygotes, whereas in a strong minority fitness of heterozygotes is increased. This review will be devoted to a consideration of the extent to which heterozygotes for a wide variety of nominally recessive diseases are subject either to an increased liability for common diseases or slight shifts of behavioral characteristics. The available evidence has been collected and will be discussed in three steps: 1. Most studies are available for phenylketonuria. For this group of diseases, a slight reduction of average ‐ especially verbal ‐ I.Q. in heterozygotes has been reported together with signs of a slightly increased cerebral irritability, a possible slight increase of risk for mental disease, and an increase of blood phenylalanine levels in stress situations. The PKU example is used to discuss methodological problems involved in such studies. 2. Other conditions for which relevant deviations in heterozygotes are possible or even likely include among others lipid storage diseases, microcephaly, myoclonus epilepsy, Wilson's disease, galaktokinase deficiency, homocystinuria, recessive myotonia and ataxia‐teleangiectasia (increased cancer risk). 3. Since heterozygotes for autosomal recessive diseases are common, it is possible that an appreciable fraction of “multifactorial” genetic liabilities for common, “constitutional” or mental disease might simply be due to heterozygosity for genes whose homozygous affects are already well known. By the same token, much of the “normal” genetic variability influencing cognitive performance (I.Q.) ‐ especially in the lower range ‐ and personality characteristics could also be caused by recessive genes in the heterozygous state.

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Heterozygote manifestation in recessive generalized myotonia

Cited by 23 publications

References 3 publications

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen).

Clinical consequences of heterozygosity for autosomal‐recessive diseases*,**

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