Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow-pancreas syndrome

被引:32
作者
van den Ouweland, JMW
de Klerk, JBC
van de Corput, MP
Dirks, RW
Raap, AK
Scholte, HR
Huijmans, JGM
Hart, LMT
Bruining, GJ
Maassen, JA
机构
[1] Leiden Univ, Med Ctr, Dept Mol Cell Biol, Sylvius Lab, NL-2333 AL Leiden, Netherlands
[2] Erasmus Univ, Sophia Childrens Hosp, Dept Paediat, Acad Hosp Rotterdam, Rotterdam, Netherlands
[3] Erasmus Univ, Acad Hosp Rotterdam, Dept Clin Genet, Rotterdam, Netherlands
关键词
mitochondria; mutation; disease; diabetes;
D O I
10.1038/sj.ejhg.5200444
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have recently diagnosed a patient with anaemia, severe tubulopathy, and diabetes mellitus. As the clinical characteristics resembled Pearson marrow-pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas in this patient, we have performed DNA analysis to seek for deletions in mtDNA. DNA analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length, with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle. No deletion could be detected in mtDNA of leukocytes from her mother and young brother, indicating the sporadic occurrence of this deletion. During culture, skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a selection against the deletion in proliferating cells. We estimate that per cell division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in situ hybridisation (FISH) and mitochondria-mediated transformation of rho(0) cells we could show inter- as well as intracellular variation in the distribution of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore, we studied the mitochondrial translation capacity in cybrid cells containing various proportions of deleted mtDNA. This result revealed a sharp threshold, around 80%, in the proportion of deleted mtDNA, above which there was strong depression of overall mitochondrial translation, and below which there was complementation of the deleted mtDNA by the wild-type DNA. Moreover, catastrophic loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.
引用
收藏
页码:195 / 203
页数:9
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