Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease.
Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor β subunit (GLRB) and the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl(-) binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na(+) affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.
Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, United Kingdom.
Eloisa
E
Carta
Seo-Kyung
SK
Chung
Victoria M
VM
James
Angela
A
Robinson
Jennifer L
JL
Gill
Nathalie
N
Remy
Jean-François
JF
Vanbellinghen
Cheney J G
CJ
Drew
Sophie
S
Cagdas
Duncan
D
Cameron
Frances M
FM
Cowan
Mireria
M
Del Toro
Gail E
GE
Graham
Adnan Y
AY
Manzur
Amira
A
Masri
Serge
S
Rivera
Emmanuel
E
Scalais
Rita
R
Shiang
Kate
K
Sinclair
Catriona A
CA
Stuart
Marina A J
MA
Tijssen
Grahame
G
Wise
Sameer M
SM
Zuberi
Kirsten
K
Harvey
Brian R
BR
Pearce
Maya
M
Topf
Rhys H
RH
Thomas
Stéphane
S
Supplisson
Mark I
MI
Rees
Robert J
RJ
Harvey
D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000235:genetics / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
C000657604:GLRA1 protein, human; C114561:GLRB protein, human; D050487:Glycine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018009:Receptors, Glycine; C493271:SLC6A5 protein, human; D005998:Glycine