title: A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2.
abstract: Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [(3)H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311-Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H(+) and Zn(2+) dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo.
authors: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Madrid 28049, Spain.
authors: Cecilio
authors: C
authors: Giménez
authors: Gonzalo
authors: G
authors: Pérez-Siles
authors: Jaime
authors: J
authors: Martínez-Villarreal
authors: Esther
authors: E
authors: Arribas-González
authors: Esperanza
authors: E
authors: Jiménez
authors: Enrique
authors: E
authors: Núñez
authors: Jaime
authors: J
authors: de Juan-Sanz
authors: Enrique
authors: E
authors: Fernández-Sánchez
authors: Noemí
authors: N
authors: García-Tardón
authors: Ignacio
authors: I
authors: Ibáñez
authors: Valeria
authors: V
authors: Romanelli
authors: Julián
authors: J
authors: Nevado
authors: Victoria M
authors: VM
authors: James
authors: Maya
authors: M
authors: Topf
authors: Seo-Kyung
authors: SK
authors: Chung
authors: Rhys H
authors: RH
authors: Thomas
authors: Lourdes R
authors: LR
authors: Desviat
authors: Carmen
authors: C
authors: Aragón
authors: Francisco
authors: F
authors: Zafra
authors: Mark I
authors: MI
authors: Rees
authors: Pablo
authors: P
authors: Lapunzina
authors: Robert J
authors: RJ
authors: Harvey
authors: Beatriz
authors: B
authors: López-Corcuera
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D005799:Genes, Dominant; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals; D021381:Protein Transport / Q000235:genetics; D013030:Spain; D006113:United Kingdom
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493271:SLC6A5 protein, human; D005998:Glycine