Emerging Concepts in Ion Channel Biophysics

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Emerging Concepts in Ion Channel Biophysics Poster Abstracts
54
46-POS Board 46
Correlation of Functional Properties of CLCN1 Variants with the Reported Inheritance of
Myotonic Symptoms
Karen Suetterlin1, Richa Sud1, Emma Matthews1, James Burge1 , Samuel McCall1, Doreen
Fialho1, Mary Sweeney1 , Henry Houlden1, Stephanie Schorge2,1, Michael G. Hanna1, Roope
Mannikko 1.
1UCL Institute of Neurology, London, United Kingdom, 2UCL 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).