Anticipation and intergenerational repeat instability in spinocerebellar ataxia type 17.
Spinocerebellar ataxia type 17 (SCA17) is caused by expansion of a CAG/CAA repeat in the TBP gene. Most pathogenic alleles are interrupted and are stably transmitted from parent to offspring without anticipation. We identified three SCA17 families with expansion of uninterrupted alleles, thus greatly increasing the number of known intergenerational transmissions of such alleles. We found that uninterrupted SCA17 alleles are unstable, associated with anticipation, and show a paternal expansion bias that increases with age. Even small increments in repeat length resulted in inordinate increases in anticipation. Anticipation was also associated with childhood presentation. Sequencing of all SCA17 alleles is required for effective genetic counseling.
Rasmussen
Astrid
A
Department of Neurogenetics and Molecular Biology, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico.
De Biase
Irene
I
Fragoso-Benítez
Marcela
M
Macías-Flores
Marco Antonio
MA
Yescas
Petra
P
Ochoa
Adriana
A
Ashizawa
Tetsuo
T
Alonso
María Elisa
ME
Bidichandani
Sanjay I
SI
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D020132:Anticipation, Genetic; D002648:Child; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008800:Mexico; D008875:Middle Aged; D010375:Pedigree; D017678:Sex Distribution; D020754:Spinocerebellar Ataxias / Q000175:diagnosis / Q000235:genetics*; D035181:TATA-Box Binding Protein / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D035181:TATA-Box Binding Protein