Identification of the microdeletion breakpoint in a GLRA1null allele of Turkish hyperekplexia patients.
Hyperekplexia (startle disease) is a hereditary motor disease caused by mutations within the GLRA1 gene (Chr. 5q33.1), which encodes the alpha1 subunit of the inhibitory glycine receptor (GlyR). While most patients are diagnosed with dominant hyperekplexia associated with point mutations within or adjacent to the channel pore, recessive hyperekplexia is less frequent. Here, we report five new pedigrees of recessive hyperekplexia in apparently unrelated families of Kurdish origin associated with a deletion of exons 1-7 of the GLRA1 gene. The deletion was identical in all families, encompassing 329 Kb of genomic sequence. No other known functional genes were involved, indicating that the GLRA1null allele is distinct from the 5q syndrome. Analysis of the DNA sequence flanking the proximal and distal breakpoint revealed no significant homology of sequences immediately adjacent to the breaks. Consensus sites for Toposiomerase II were detected close to the breakpoint compatible with an illegitimate recombination event. No heterozygous carriers of the deletion allele were detected by screening of 500 individuals from the southeastern Mediterranean region belonging to four different ethnic groups. Hence, the identical nature of the breakpoint junction in all patients and carriers suggests a founder mutation in an ethnic population originating from Turkey.
Becker
Kristina
K
Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany.
Hohoff
Carsten
C
Schmitt
Bernhard
B
Christen
Hans-Jürgen
HJ
Neubauer
Bernd A
BA
Sandrieser
Torsten
T
Becker
Cord-Michael
CM
D000483:Alleles; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D018009:Receptors, Glycine / Q000235:genetics*; D016750:Stiff-Person Syndrome / Q000208:ethnology / Q000235:genetics*; D014421:Turkey
C000657604:GLRA1 protein, human; D018009:Receptors, Glycine