Hyperekplexia (startle disease): a novel mutation (S270T) in the M2 domain of the GLRA1 gene and a molecular review of the disorder.
BACKGROUND
We report on a novel mutation (S270T) in the M2 domain of the GLRA1 (alpha subunit of the glycine receptor) gene causing autosomal dominant hyperekplexia in a neonate, the mother and maternal uncle. All affected members showed the typical clinical features of the disorder. This novel S270T (T1188A) mutation is located in the boundary of the transmembrane M2 domain of the GLRA1 protein, close to other previously reported mutations. Mutations in this 'hot spot' domain of GLRA1 are frequent in autosomal dominant hyperekplexia but are not usually seen in the autosomal recessive form of the disease in which both the M1 and the carboxy terminal domains have been implicated.


METHODS
Genomic DNA was extracted by standard procedures from peripheral blood leukocytes and exon 6 of the GLRA1 gene was amplified using primers and PCR conditions. A complete sequence analysis of the fragment was performed. DNA sequences were analyzed both by direct observation of the electropherogram and by comparison with the published sequence.


RESULTS
The proband had metabolic acidosis, which was probably related to continuous contractions of somatic muscles and intractable hypertonia. Data seem to show a direct relationship between the mechanism of inheritance of the disorder and the location of the molecular defect. The patients showed almost all the clinical signs of hyperekplexia: exaggerated startle response, muscle hypertonia in response to unexpected tactile and/or auditory stimuli, hyperexcitability, and sudden falls.
Lapunzina
Pablo
P
Department of Medical Genetics, Hospital Universitario La Paz, Madrid, Spain.
Sánchez
Juan M
JM
Cabrera
Marta
M
Moreno
Ana
A
Delicado
Alicia
A
de Torres
Maria L
ML
Mori
Angeles M
AM
Quero
José
J
Lopez Pajares
Isidora
I
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D018009:Receptors, Glycine / Q000737:chemistry / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
C000657604:GLRA1 protein, human; D018009:Receptors, Glycine