Background: Hyperekplexia, also known as startle disease or stiff-person syndrome, is a neurological condition characterized by neonatal hypertonia and a highly exaggerated startle reflex. Genetic studies have linked mutations in the gene encoding glycine receptor α1 (GLRA1) with hereditary hyperekplexia.
Methods: We analyzed four Turkish families with a history of hyperekplexia. Genomic DNA was obtained from members of these families, and the entire coding sequence of GLRA1 was amplified by PCR followed by the sequencing of PCR products. DNA sequences were analyzed by direct observation using an electropherogram and compared with a published reference sequence.
Results: We identified three novel mutations in GLRA1. These included a large deletion removing the first 7 of 9 exons, a single-base deletion in exon 8 that results in protein truncation immediately after the deletion, and a missense mutation in exon 7 causing a tryptophan-to-cysteine change in the first transmembrane domain (M1). These mutant alleles have some distinct features as compared to previously identified GLRA1 mutations. Our data provides further evidence for mutational heterogeneity in GLRA1. The new mutant alleles reported here should advance our understanding of the etiology of hyperekplexia.
Clonazepam Piracetam Glycine Receptor Turkish Family Startle Disease
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.
We thank Y. Ilkin for translating the Patient Consent Form into Turkish, and K. Petras for DNA isolation. We also thank the hyperekplexia patients and their families for participating in this study.
This study was supported by the Howard Hughes Medical Institute (to Drs Gilbert and Lahn), and the Searle Scholarship and Burroughs Wellcome Career Award (to Dr Lahn).
The authors have no potential conflicts of interest directly relevant to the content of this study.
Rees MI, Andrew M, Jawad S, et al. Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor. Hum Mol Genet 1994; 3: 2175–9PubMedCrossRefGoogle Scholar
Vergouwe MN, Tijssen MA, Peters AC, et al. Hyperekplexia phenotype due to compound heterozygosity for GLRA1 gene mutations. Ann Neurol 1999; 46: 634–8PubMedCrossRefGoogle Scholar
Tijssen MA, Vergouwe MN, van Dijk JG, et al. Major and minor form of hereditary hyperekplexia. Mov Disord 2002; 17(4): 826–30PubMedCrossRefGoogle Scholar
Ryan SG, Sherman SL, Terry JC, et al. Startle disease, or hyperekplexia: response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis. Ann Neurol 1992; 31: 663–8PubMedCrossRefGoogle Scholar
Brune W, Weber RG, Saul B, et al. A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors. Am J Hum Genet 1996; 58: 989–97PubMedGoogle Scholar
Rees MI, Lewis TM, Vafa B, et al. Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia. Hum Genet 2001; 109: 267–70PubMedCrossRefGoogle Scholar
Shiang R, Ryan SG, Zhu YZ, et al. Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 1993; 5: 351–8PubMedCrossRefGoogle Scholar
Shiang R, Ryan SG, Zhu YZ, et al. Mutational analysis of familial and sporadic hyperekplexia. Ann Neurol 1995; 38: 85–91PubMedCrossRefGoogle Scholar
Elmslie FV, Hutchings SM, Spencer V, et al. Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis. J Med Genet 1996; 33: 435–6PubMedCrossRefGoogle Scholar
Milani N, Dalpra L, del Prete A, et al. A novel mutation (Gln266→His) in the alpha 1 subunit of the inhibitory glycine-receptor gene (GLRA1) in hereditary hyperekplexia. Am J Hum Genet 1996; 58: 420–2PubMedGoogle Scholar
Saul B, Kuner T, Sobetzko D, et al. Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating. J Neurosci 1999; 19: 869–77PubMedGoogle Scholar
del Giudice EM, Coppola G, Bellini G, et al. A mutation (V260M) in the middle of the M2 pore-lining domain of the glycine receptor causes hereditary hyperekplexia. Eur J Hum Genet 2001; 9: 873–6PubMedCrossRefGoogle Scholar
Humeny A, Bonk T, Becker K, et al. A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation as a determinant of cellular glycine receptor trafficking. Eur J Hum Genet 2002; 10: 188–96PubMedCrossRefGoogle Scholar
del Giudice EM, Coppola G, Bellini G, et al. 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. J Med Genet 2003; 40: e71CrossRefGoogle Scholar
Rees MI, Lewis TM, Kwok JB, et al. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Mol Genet 2002; 11: 853–60PubMedCrossRefGoogle Scholar
Lapunzina P, Sanchez JM, Cabrera M, et al. Hyperekplexia (startle disease): a novel mutation (S270T) in the M2 domain of the GLRA1 gene and a molecular review of the disorder. Mol Diagn 2003; 7: 125–8PubMedCrossRefGoogle Scholar
Kwok JB, Raskin S, Morgan G, et al. Mutations in the glycine receptor alphal subunit (GLRA1) gene in hereditary hyperekplexia pedigrees: evidence for non-penetrance of mutation Y279C. J Med Genet 2001; 38: e17PubMedCrossRefGoogle Scholar
Seri M, Bolino A, Galietta LJ, et al. Startle disease in an Italian family by mutation (K276E): the alpha-subunit of the inhibiting glycine receptor. Hum Mutat 1997; 9: 185–7PubMedCrossRefGoogle Scholar
Cengiz B, Odabasi Z, Ozdag F, et al. Essential startle disease may not be a uniform entity. Clin Electroencephalogr 2001; 32: 92–5PubMedGoogle Scholar
Kato M, Das S, Petras K, et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 2004; 23(2): 147–59PubMedCrossRefGoogle Scholar
Rees MI, Harvey K, Ward H, et al. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. J Biol Chem 2003; 278: 24688–96PubMedCrossRefGoogle Scholar
Schmieden V, Kuhse J, Betz H. Mutation of glycine receptor subunit creates beta-alanine receptor responsive to GABA. Science 1993; 262: 256–8PubMedCrossRefGoogle Scholar
Griffon N, Buttner C, Nicke A, et al. Molecular determinants of glycine receptor subunit assembly. EMBO J 1999; 18: 4711–21PubMedCrossRefGoogle Scholar
Vafa B, Lewis TM, Cunningham AM, et al. Identification of a new ligand binding domain in the alphal subunit of the inhibitory glycine receptor. J Neurochem 1999; 73: 2158–66PubMedGoogle Scholar
Lynch JW, Rajendra S, Pierce KD, et al. Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel. EMBO J 1997; 16: 110–20PubMedCrossRefGoogle Scholar
Langosch D, Herbold A, Schmieden V, et al. Importance of Arg-219 for correct biogenesis of alpha 1 homooligomeric glycine receptors. FEBS Lett 1993; 336: 540–4PubMedCrossRefGoogle Scholar
Rajendra S, Lynch JW, Pierce KD, et al. Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor. J Biol Chem 1994; 269: 18739–42PubMedGoogle Scholar
Lewis TM, Sivilotti LG, Colquhoun D, et al. Properties of human glycine receptors containing the hyperekplexia mutation alphal (K276E), expressed in Xenopus oocytes. J Physiol 1998; 507 (Pt 1): 25–40PubMedCrossRefGoogle Scholar
Moorhouse AJ, Jacques P, Barry PH, et al. The startle disease mutation Q266H, in the second transmembrane domain of the human glycine receptor, impairs channel gating. Mol Pharmacol 1999; 55: 386-95PubMedGoogle Scholar