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Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2022-08-05 , DOI: 10.1016/j.ajhg.2022.06.014
Hemanth Tummala 1 , Amanda Walne 1 , Roberto Buccafusca 2 , Jenna Alnajar 1 , Anita Szabo 3 , Peter Robinson 4 , Allyn McConkie-Rosell 5 , Meredith Wilson 6 , Suzanne Crowley 7 , Veronica Kinsler 8 , Anna-Maria Ewins 9 , Pradeepa M Madapura 1 , Manthan Patel 1 , Nikolas Pontikos 3 , Veryan Codd 10 , Tom Vulliamy 1 , Inderjeet Dokal 11
Affiliation  

Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.



中文翻译:

种系胸苷酸合酶缺乏影响核苷酸代谢并导致先天性角化不良

先天性角化不良 (DC) 是一种遗传性骨髓衰竭疾病,其特征为皮肤粘膜异常三联征,包括异常皮肤色素沉着、指甲营养不良和口腔白斑。尽管鉴定了几种导致 DC 的遗传变异,但仍有很大一部分先证者没有进行分子诊断。在由八个独立的 DC 影响的家族组成的队列中,我们在编码胸苷酸合酶 ( TYMS )的基因中鉴定出了一系列显着的杂合种系变异。尽管遗传似乎是常染色体隐性遗传,但每个家族中的一个亲本都具有野生型TYMS编码序列。靶向基因组测序鉴定了从另一亲本继承的天然存在的 TYMS 反义调节因子ENOSF1 (烯醇化酶超家族 1)中的特定单倍型和罕见变异。来自受影响先证者的类淋巴母细胞具有严重的 TYMS 缺陷、细胞脱氧核糖核苷酸三磷酸库改变以及对 TYMS 特异性抑制剂 5-氟尿嘧啶过敏。核苷酸代谢途径中的这些缺陷导致基因毒性应激、转录缺陷和端粒维持异常。对受影响先证者细胞的基因拯救研究表明, TYMS的转录后上位沉默是通过升高的ENOSF1发生的。这些由TYMS-ENOSF1基因座处的种系双基因变异组合产生的细胞和分子异常代表了这些受影响个体中 DC 因果关系的独特致病途径,而以单一方式携带这些变异的父母则不受影响。

更新日期:2022-08-05
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