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Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10 |
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| Authors: | Matsuura Tohru Fang Ping Lin Xi Khajavi Mehrdad Tsuji Kuniko Rasmussen Astrid Grewal Raji P Achari Madhureeta Alonso Maria E Pulst Stefan M Zoghbi Huda Y Nelson David L Roa Benjamin B Ashizawa Tetsuo |
| Affiliation: | 1 Department of Neurology, The University of Texas Medical Branch, Galveston 2 Department of Molecular and Human Genetics, The University of Texas Medical Branch, Galveston 3 Department of Pediatrics, The University of Texas Medical Branch, Galveston 4 Howard Hughes Medical Institute, Baylor College of Medicine, The University of Texas Medical Branch, Galveston 5 Department of Veterans Affairs Medical Center, The University of Texas Medical Branch, Galveston 6 private practice, Houston, The University of Texas Medical Branch, Galveston 7 Department of Neurology, The University of Texas Medical Branch, Galveston 8 Department of Neurogenetics and Molecular Biology, Instituto Nacional de Neurología y Neurocirugía, México City 9 New Jersey Neuroscience Institute, Seton Hall University, Edison 10 Department of Neurology, Rose Moss Laboratory for Parkinson and Neurodegenerative Diseases, Burns and Allen Research Institute, Division of Neurology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles |
| Abstract: | Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized by ataxia, seizures, and anticipation. It is caused by an expanded ATTCT pentanucleotide repeat in intron 9 of a novel gene, designated "SCA10." The ATTCT expansion in SCA10 represents a novel class of microsatellite repeat and is one of the largest found to cause human diseases. The expanded ATTCT repeat is unstably transmitted from generation to generation, and an inverse correlation has been observed between size of repeat and age at onset. In this multifamily study, we investigated the intergenerational instability, somatic and germline mosaicism, and age-dependent repeat-size changes of the expanded ATTCT repeat. Our results showed that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission resulted in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal cells, and sperm have a variable degree of mosaicism in ATTCT expansion; (3) the length of the expanded repeat was not observed to change in individuals over a 5-year period; and (4) clinically determined anticipation is sometimes associated with intergenerational contraction rather than expansion of the ATTCT repeat. |
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