Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene.
Myotonic dystrophy type 1 is caused by the expansion of a CTG repeat in the 3' UTR of the DMPK gene. A length exceeding 50 CTG triplets is pathogenic. Intermediate alleles with 35-49 triplets are not disease-causing but show instability in intergenerational transmissions. We report on the identification of multiple patients with different patterns of CCG and CTC interruptions in the DMPK CTG repeat tract that display unique intergenerational instability. In patients bearing interrupted expanded alleles, the location of the interruptions changed dramatically between generations and the repeats tended to contract. The phenotype for these patients corresponded to the classical form of the disease, but in some cases without muscular dystrophy and possibly with a later onset than expected. Symptomatic patients bearing interrupted intermediate length repeat tracts were also identified, although the role of the interruptions in their phenotype remains unclear. The identification of interruptions in the DMPK repeat has important consequences for molecular genetic testing where they can lead to false negative conclusions.
Musova
Zuzana
Z
Department of Biology and Medical Genetics, Charles University 2nd Medical School and University Hospital Motol, Prague, Czech Republic. zuzana.musova@lfmotol.cuni.cz
Mazanec
Radim
R
Krepelova
Anna
A
Ehler
Edvard
E
Vales
Jiri
J
Jaklova
Radka
R
Prochazka
Tomas
T
Koukal
Petr
P
Marikova
Tatana
T
Kraus
Josef
J
Havlovicova
Marketa
M
Sedlacek
Zdenek
Z
D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D042822:Genomic Instability / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D065636:Myotonin-Protein Kinase; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics*; D055815:Young Adult
C585517:DMPK protein, human; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases