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DOI 10.1016/j.neuron.2020.11.005

Медицинская библиотека · Neuron · 2020

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Dewan Ramita, Chia Ruth, Ding Jinhui, Hickman Richard A, Stein Thor D, Abramzon Yevgeniya, Ahmed Sarah, Sabir Marya S, Portley Makayla K, Tucci Arianna, Ibáñez Kristina, Shankaracharya F N U, Keagle Pamela, Rossi Giacomina, Caroppo Paola, Tagliavini Fabrizio, Waldo Maria L, Johansson Per M, Nilsson Christer F, American Genome Center (TAGC), FALS Sequencing Consortium, Genomics England Research Consortium, International ALS/FTD Genomics Consortium (iAFGC), International FTD Genetics Consortium (IFGC), International LBD Genomics Consortium (iLBDGC), NYGC ALS Consortium, PROSPECT Consortium, Rowe James B, Benussi Luisa, Binetti Giuliano, Ghidoni Roberta, Jabbari Edwin, Viollet Coralie, Glass Jonathan D, Singleton Andrew B, Silani Vincenzo, Ross Owen A, Ryten Mina, Torkamani Ali, Tanaka Toshiko, Ferrucci Luigi, Resnick Susan M, Pickering-Brown Stuart, Brady Christopher B, Kowal Neil, Hardy John A, Van Deerlin Vivianna, Vonsattel Jean Paul, Harms Matthew B, Morris Huw R, Ferrari Raffaele, Landers John E, Chiò Adriano, Gibbs J Raphael, Dalgard Clifton L, Scholz Sonja W, Traynor Bryan J

СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Для цитирования: Dewan Ramita, Chia Ruth, Ding Jinhui, Hickman Richard A, Stein Thor D, Abramzon Yevgeniya, Ahmed Sarah, Sabir Marya S, Portley Makayla K, Tucci Arianna, Ibáñez Kristina, Shankaracharya F N U, Keagle Pamela, Rossi Giacomina, Caroppo Paola, Tagliavini Fabrizio, Waldo Maria L, Johansson Per M, Nilsson Christer F, American Genome Center (TAGC), FALS Sequencing Consortium, Genomics England Research Consortium, International ALS/FTD Genomics Consortium (iAFGC), International FTD Genetics Consortium (IFGC), International LBD Genomics Consortium (iLBDGC), NYGC ALS Consortium, PROSPECT Consortium, Rowe James B, Benussi Luisa, Binetti Giuliano, Ghidoni Roberta, Jabbari Edwin, Viollet Coralie, Glass Jonathan D, Singleton Andrew B, Silani Vincenzo, Ross Owen A, Ryten Mina, Torkamani Ali, Tanaka Toshiko, Ferrucci Luigi, Resnick Susan M, Pickering-Brown Stuart, Brady Christopher B, Kowal Neil, Hardy John A, Van Deerlin Vivianna, Vonsattel Jean Paul, Harms Matthew B, Morris Huw R, Ferrari Raffaele, Landers John E, Chiò Adriano, Gibbs J Raphael, Dalgard Clifton L, Scholz Sonja W, Traynor Bryan J. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.. Neuron. 2020. DOI: 10.1016/j.neuron.2020.11.005.

Предметные рубрики MeSH

Amyotrophic Lateral SclerosisDNA Repeat ExpansionFrontotemporal DementiaHumansHuntingtin ProteinMutationWhole Genome Sequencing
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