Abstract
Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity. The autosomal-dominant form of PEO is genetically heterogeneous. Recently, causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B). Despite these findings, putative mutations remain unknown in half of the subjects with PEO. We report the identification, by exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA. DNA2 encodes a helicase/nuclease family member that is most likely involved in mtDNA replication, as well as in the long-patch base-excision repair (LP-BER) pathway. Invitro biochemical analysis of purified mutant proteins revealed a severe impairment of nuclease, helicase, and ATPase activities. These results implicate human DNA2 and the LP-BER pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance.
Highlights
Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity
Causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B)
By exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA
Summary
Dario Ronchi,[1,10] Alessio Di Fonzo,[1,10] Weiqiang Lin,[2,10] Andreina Bordoni,[1] Changwei Liu,[2] Elisa Fassone,[3] Serena Pagliarani,[1] Mafalda Rizzuti,[1] Li Zheng,[2] Massimiliano Filosto,[4] Maria Teresa Ferro ,5 Michela Ranieri,[1] Francesca Magri,[1] Lorenzo Peverelli,[7] Hongzhi Li,[8] Yate-Ching Yuan,[8] Stefania Corti,[1,6] Monica Sciacco,[7] Maurizio Moggio,[7] Nereo Bresolin,[1,6,9] Binghui Shen,2,* and Giacomo Pietro Comi1,6,*. Despite the discovery of causative mutations in several genes, a firm diagnosis can be achieved, at best, in half of patients.[5] To identify genetic defects in individuals who showed signs of mtDNA instability, we performed wholeexome next-generation sequencing[6] in a family in which two siblings (probands 1 [P1] and 2 [P2]) developed progressive myopathy with evidence of muscle mitochondrial dysfunction, as disclosed by histochemical analysis of skeletal muscle biopsy (Figure S1, available online). Probands 3 (P3) and 4 (P4), we identified missense variants c.937A>G (exon 5) and c.2167G>A (exon 12), which lead to protein changes p.Lys313Glu and p.Val723Ile, respectively Both subjects presented with adult-onset mitochondrial disease that consisted of ptosis and progressive myopathy. Myalgia, dysphoria, exertional normal COXÀ (5%), RRF fiber hypotrophy diplopia, myalgia, mild ophthalmoplegia ophthalmoplegia episodic dyspnea, mild ptosis, childhood limb-girdle weakness depression, hyperthyroidism, M/N COXÀ (4%), type II
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