Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

46-POS Board 46 Correlation of Functional Properties of CLCN1 Variants with the Reported Inheritance of Myotonic Symptoms Karen Suetterlin 1 , Richa Sud 1 , Emma Matthews 1 , James Burge 1 , Samuel McCall 1 , Doreen Fialho 1 , Mary Sweeney 1 , Henry Houlden 1 , Stephanie Schorge 2,1 , Michael G. Hanna 1 , Roope Mannikko 1 . 1 UCL Institute of Neurology, London, United Kingdom, 2 UCL Instutute of neurology, London, United Kingdom. Myotonia Congenita (MC) is caused by mutations in the CLCN1 gene that encodes the muscle chloride channel ClC-1. MC is caused by loss-of-function mutations that can be dominantly or recessively inherited. Accuracy of diagnosis and genetic counselling of MC for novel missense mutations can be challenging based on genetic information alone. We performed functional characterization, as a part of diagnostic set up, for 89 ClC-1 missense variants identified in 221 probands referred to our national diagnostic centre. To assess the value of functional expression we correlated the functional data with available clinical and genetic information. Functional properties were assessed in Xenopus laevis oocytes using two-electrode voltage clamp. The vast majority of variants showed properties that were either wild-type-like, full loss- of-function, or had shifted voltage dependence of activation. For two variants the voltage dependence of activation could not be described with Boltzmann function and one showed dramatically increased baseline activity. In simulated heterozygous conditions the loss-of- function variants showed either wild-type-like properties or shifted voltage dependence of activation. The correlation of functional properties with inheritance pattern of clinical symptoms was excellent. For example, almost 90% of the variants with recessive functional properties were found in families categorised as recessive. We also mapped the variants onto a model of ClC-1 to identify regions associated with a functional phenotype or an inheritance pattern. We found 42% of variants in the first half of the transmembrane region were associated with dominant inheritance versus 2% outside this region. In contrast, variants in the cytoplasmic regions were significantly more likely to be categorised as uncertain pathogenicity (p=0.004).

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