Early-onset familial hemiplegic migraine due to a novel SCN1A mutation

TY - JOUR

T1 - Early-onset familial hemiplegic migraine due to a novel SCN1A mutation

AU - Fan, Chunxiang

AU - Wolking, Stefan

AU - Lehmann-Horn, Frank

AU - Hedrich, Ulrike Bs

AU - Freilinger, Tobias

AU - Lerche, Holger

AU - Borck, Guntram

AU - Kubisch, Christian

AU - Jurkat-Rott, Karin

N1 - © International Headache Society 2016.

PY - 2016/10

Y1 - 2016/10

N2 - INTRODUCTION: Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na(+) channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family.METHODS: A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with β1 and β2 subunits.RESULTS AND CONCLUSIONS: We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.

AB - INTRODUCTION: Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na(+) channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family.METHODS: A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with β1 and β2 subunits.RESULTS AND CONCLUSIONS: We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.

U2 - 10.1177/0333102415608360

DO - 10.1177/0333102415608360

M3 - SCORING: Journal article

C2 - 26763045

VL - 36

SP - 1238

EP - 1247

JO - CEPHALALGIA

JF - CEPHALALGIA

SN - 0333-1024

IS - 13

ER -