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DOI 10.1056/nejmoa1806627

Медицинская библиотека · The New England journal of medicine · 2019

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

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Аннотация

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.

Для цитирования: 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. Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS.. The New England journal of medicine. 2019. DOI: 10.1056/nejmoa1806627.

Предметные рубрики MeSH

Amino Acid Metabolism, Inborn ErrorsAtaxiaAtrophyCerebellumChild, PreschoolDevelopmental DisabilitiesFemaleGenotypeGlutaminaseGlutamineHumansMaleMicrosatellite RepeatsMutationPhenotypePolymerase Chain ReactionWhole Genome Sequencing
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