Utyro Olga, Perła-Kaján Joanna, Kubalska Jolanta, Graban Ałła, Jakubowski Hieronim
Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632, Poznań, Poland; Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704, Poznań, Poland.
Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632, Poznań, Poland.
Free Radic Biol Med. 2020 Nov 20;160:219-226. doi: 10.1016/j.freeradbiomed.2020.07.036. Epub 2020 Aug 5.
Telomere shortening and mitochondrial DNA (mtDNA) copy number are associated with human disease and a reduced life span. Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step in metabolic conversion of homocysteine (Hcy) to cysteine. Mutations in the CBS gene cause CBS deficiency, a rare recessive metabolic disease, manifested by severe hyperhomocysteinemia (HHcy) and thromboembolism, which ultimately reduces the life span. However, it was not known whether telomere shortening or mtDNA is involved in the pathology of human CBS deficiency. We quantified leukocyte telomere length (TL), mtDNA copy number, and plasma Hcy levels in CBS patients (n = 23) and in sex- and age-matched unaffected CBS control individuals (n = 28) 0.08-57 years old. We found that TL was significantly increased in severely HHcy CBS female patients but unaffected in severely HHcy CBS male patients, relative to the corresponding CBS controls who had normal plasma Hcy levels. In multiple regression analysis TL was associated with CBS genotype in women but not in men. MtDNA copy number was not significantly affected by the CBS genotype. Taken together, these findings identify the CBS gene as a new locus in human DNA that affects TL in women and illustrate a concept that a housekeeping metabolic gene can be involved in telomere biology. Our findings suggest that neither telomere shortening nor reduced mtDNA copy number contribute to the reduced life span in CBS patients.
端粒缩短和线粒体DNA（mtDNA）拷贝数与人类疾病及寿命缩短相关。胱硫醚β-合酶（CBS）是一种管家酶，催化同型半胱氨酸（Hcy）代谢转化为半胱氨酸的第一步。CBS基因突变会导致CBS缺乏症，这是一种罕见的隐性代谢疾病，表现为严重的高同型半胱氨酸血症（HHcy）和血栓栓塞，最终缩短寿命。然而，尚不清楚端粒缩短或mtDNA是否参与人类CBS缺乏症的病理过程。我们对23例CBS患者及28例年龄和性别匹配的未受影响的CBS对照个体（年龄在0.08至57岁之间）的白细胞端粒长度（TL）、mtDNA拷贝数和血浆Hcy水平进行了量化。我们发现，与血浆Hcy水平正常的相应CBS对照相比，严重HHcy的CBS女性患者的TL显著增加，但严重HHcy的CBS男性患者的TL未受影响。在多元回归分析中，TL在女性中与CBS基因型相关，而在男性中则不然。mtDNA拷贝数未受CBS基因型的显著影响。综上所述，这些发现确定CBS基因为人类DNA中影响女性TL的一个新位点，并阐明了一个管家代谢基因可参与端粒生物学的概念。我们的研究结果表明，端粒缩短和mtDNA拷贝数减少均未导致CBS患者寿命缩短。
