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Mutations in the glycine receptor α1 subunit (GLRA1) gene in hereditary hyperekplexia pedigrees: evidence for non-penetrance of mutation Y279C
  1. John B J Kwoka,
  2. Salmo Raskinb,
  3. Graeme Morganc,
  4. Sergio Antonio Antoniukd,
  5. Isac Brukd,
  6. Peter R Schofielda
  1. aGarvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia, bLaboratorio Genetika, Alameda Augusto Stellfeld 1516, Curitiba, Parana 80730-150, Brazil, cDepartment of Medical Genetics, Prince of Wales Children's Hospital, High Street, Randwick, Sydney, NSW 2031, Australia, dDivision of Neuropediatrics, Pediatrics Department, Hospital das Clinicas, Universidade Federal do Parano, Curitiba, Parana 80730-150 Brazil
  1. Professor Schofield, p.schofield{at}

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Editor—Hereditary hyperekplexia, or familial startle disease (OMIM 149400), is a rare neurological disease that is characterised by marked muscular hypotonia in affected infants and an exaggerated response or “startle” reflex to an unexpected stimulus. Positional candidate analysis has successfully identified the gene coding for the α1 subunit of the inhibitory glycine receptor (GLRA1) on chromosome 5q33-35 as the disease gene.1 The glycine receptor (GlyR) is a ligand gated chloride channel which mediates synaptic inhibition in the spinal cord and other brain regions.2 The majority of inherited mutations have been found in exons 6 and 7 of theGLRA1 gene, which code for the first and second transmembrane (TM) domains of the receptor. At present, six missense mutations, P250T,3 Q266H,4R271L,1 ,6 R271Q,1 ,6 K276E,5and Y279C,6 are inherited in a dominant manner. Two mutations, I244N7 and a deletion of exon 1 to 6 of theGLRA1 gene,8 can also result in a recessive phenotype, as detected in affected offspring of consanguineous parents. Finally, there are compound mutations (R252H and R392H) which, when inherited from the two parental alleles, give rise to hyperekplexia.9 In this report, we analysed theGLRA1 gene as the candidate for the disease locus in two families with hereditary hyperekplexia.

Case reports

The first pedigree (Fam-1) contains 20 members over three generations with 10 affected subjects (fig 1A). The female proband (III.13) from family 1 was prone to fall …

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