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Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS.

van Kuilenburg, André B P; Tarailo-Graovac, Maja; Richmond, Phillip A; Drögemöller, Britt I; Pouladi, Mahmoud A; Leen, René; Brand-Arzamendi, Koroboshka; Dobritzsch, Doreen; Dolzhenko, Egor; Eberle, Michael A; Hayward, Bruce; Jones, Meaghan J; Karbassi, Farhad; Kobor, Michael S; Koster, Janet; Kumari, Daman; Li, Meng; MacIsaac, Julia; McDonald, Cassandra; Meijer, Judith; Nguyen, Charlotte; Rajan-Babu, Indhu-Shree; Scherer, Stephen W; Sim, Bernice; Trost, Brett; Tseng, Laura A; Turkenburg, Marjolein; van Vugt, Joke J F A; Veldink, Jan H; Walia, Jagdeep S; Wang, Youdong; van Weeghel, Michel; Wright, Galen E B; Xu, Xiaohong; Yuen, Ryan K C; Zhang, Jinqiu; Ross, Colin J; Wasserman, Wyeth W; Geraghty, Michael T; Santra, Saikat; Wanders, Ronald J A; Wen, Xiao-Yan; Waterham, Hans R; Usdin, Karen; van Karnebeek, Clara D M.
N Engl J Med; 380(15): 1433-1441, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30970188
We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.
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