Intergenerational Instability of the Expanded CTG Repeat in the DMPK Gene: Studies in Human Gametes and Preimplantation Embryos

Abstract

The CTG repeat at the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene shows marked intergenerational and somatic instability in patients with myotonic dystrophy (DM1), when the repeat is expanded to more than approximately 55 repeats. Intensive research has yielded some insights into the timing and mechanism of these intergenerational changes: (1) increases in expansion sizes occur during gametogenesis but probably not during meiosis, (2) the marked somatic mosaicism becomes apparent from the 2nd trimester of development onward and increases during adult life, and (3) DNA repair mechanisms are involved. We have performed preimplantation genetic diagnosis for DM1 since 1995, which has given us the unique opportunity to study the expanded CTG repeat in affected embryos and in gametes from affected patients. We were able to demonstrate significant increases in the number of repeats in embryos from female patients with DM1 and in their immature and mature oocytes, whereas, in spermatozoa and embryos from male patients with DM1, smaller increases were detected. These data are in concordance with data on other tissues from adults and fetuses and fill a gap in our knowledge of the behavior of CTG triplet expansions in DM1.

Microsatellite Polymorphisms in DNA Repair GenesXRCC1, XRCC3andXRCC5in Patients with Gynecological Tumors: Association with Late Clinical Radiosensitivity and Cancer Incidence

“…Repeat units are gained and lost by DNA replication slippage, a mutation mechanism that results from the transient dissociation of the replicating DNA strands followed by misaligned reassociation (14,15). Expansions of triplet repeats are the underlying cause of several genetic diseases such as myotonic dystrophy, Huntington's disease and fragile X syndrome (16)(17)(18). Furthermore, microsatellites are the molecular targets for malfunctioning repair and replication proteins in diseases such as hereditary non-polyposis colorectal carcinoma (HNPCC), where there is a defect in mismatch repair, and Bloom's syndrome, where a DNA helicase homologue is defective (19,20).…”

Identification of Novel Microsatellite Markers <1 Mb from the HTT CAG Repeat and Development of a Single-Tube Tridecaplex PCR Panel of Highly Polymorphic Markers for Preimplantation Genetic Diagnosis of Huntington Disease

“…Somatic mosaicism of the HTT CAG repeat expansion has been reported in specific cell types in HD patients, including sperm cells (31,32 ), although repeat size mosaicism has not been observed before the second trimester of pregnancy (33,34 ). Because the tridecaplex marker panel only provides linkage data to track the normal and mutant (expanded) alleles, the diagnostic accuracy of this assay will not be affected by any repeat expansion mosaicism, even if it were to occur at this early stage of embryonic development.…”

“…3 (3, 4 ). HTT alleles are classified based on the number of CAG repeats: normal (Յ26 CAGs), intermediate (27)(28)(29)(30)(31)(32)(33)(34)(35), HD-causing with reduced-penetrance (36 -39 CAGs), and HDcausing with full-penetrance (Ն40 CAGs). Clinical symptoms of HD progress gradually, usually with cognitive and psychiatric manifestations appearing first followed by movement abnormalities and, finally, death (5,6 ).…”

Patients with primary cataract as a genetic pool of DMPK protomutation

“…The molecular mechanisms that determine the instability of triplet repeats during meiosis are unclear, implicating not only meiotic recombination but also DNA replication and repair (Pearson 2003;Malter et al 1997;De Temmerman et al 2004), CpG islands methylation, or its absence in the flanking region of the DMPK repeats and other epigenetic germline-specific modifications (Lemmers et al 2004), the involvement of nucleosomes (Wang et al 1994), and the defect in the DNA mismatch repair trans-acting mechanism (Kramer et al 1996). Also, especially in DM1, a role for the perturbation of replication in instability is strongly supported (Yang et al 2003).…”