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  • A novel mutation (R218Q) at the boundary between the N-terminal and the first transmembrane domain of the glycine receptor in a case of sporadic hyperekplexia

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A novel mutation (R218Q) at the boundary between the N-terminal and the first transmembrane domain of the glycine receptor in a case of sporadic hyperekplexia
  1. E Miraglia Del Giudice1,5,
  2. G Coppola2,5,
  3. G Bellini2,5,
  4. P Ledaal3,
  5. J M Hertz4,
  6. A Pascotto2,5
  1. 1Department of Paediatrics, Second University of Naples, Naples, Italy
  2. 2Chair of Child and Adolescent Neuropsychiatry, Second University of Naples, Naples, Italy
  3. 3Department of Paediatrics, Sonderborg Hospital, Sonderborg, Denmark
  4. 4Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  5. 5Interuniversity Centre for Neuroscience Research (CIRN), Naples, Italy
  1. Correspondence to:
 Professor A Pascotto, C Neuropsichiatria Infantile, 2° Policlinico, Via S Pansini 5, 80131, Napoli, Italy; 
 antonio.pascotto{at}unina2.it

https://doi.org/10.1136/jmg.40.5.e71

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    Hyperekplexia or startle disease (STHE, OMIM 149400) is a rare neurological disorder characterised by neonatal generalised muscular hypertonia followed by a period of generalised stiffness and by an exaggerated startle response to sudden external stimuli that persists throughout life.1 Hyperekplexia is usually inherited in an autosomal dominant manner although there is also evidence for a recessive form.1,2 Both forms are caused by mutations in the same gene, GLRA1, mapping on 5q31.2 and encoding for the α1 subunit of the inhibitory glycine receptor chloride channel.1–10 Recently, it has been shown that glycine receptor beta subunit mutations can also lead to hyperekplexia.11

    Glycine receptor (GlyR) belongs to the ligand gated ion channel receptor superfamily (LGICs), which includes α-aminobutyric acid, acetylcholine, and 5-hydroxytryptamine receptors and are localised in the postsynaptic membrane. All share a common pentameric structure that spans the membrane, comprising homologous subunits arranged in a ring to form a central ion conducting pore. In the case of GlyR, the 3α1–2β complex is selective for chloride ions.12

    Each subunit is made up of a large glycosylated N-terminal extracellular domain, a short extracellular C-terminus, and four hydrophobic transmembrane spans (M1-M4), separated by two short hydrophilic loops M1-M2 (intracellular) and M2-M3 (extracellular) flanking the pore lining M2 domain, and by a long, extracellular, leucine rich M3-M4 loop.13,14

    Considering both dominant and recessive hyperekplexia cases, 15, mostly missense, …

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