eprintid: 1368873 rev_number: 42 eprint_status: archive userid: 608 dir: disk0/01/36/88/73 datestamp: 2012-10-20 19:03:09 lastmod: 2021-12-01 23:29:39 status_changed: 2012-10-20 19:03:09 type: article metadata_visibility: show item_issues_count: 0 creators_name: Alston, CL creators_name: Davison, JE creators_name: Meloni, F creators_name: van der Westhuizen, FH creators_name: He, L creators_name: Hornig-Do, H-T creators_name: Peet, AC creators_name: Gissen, P creators_name: Goffrini, P creators_name: Ferrero, I creators_name: Wassmer, E creators_name: McFarland, R creators_name: Taylor, RW title: Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency ispublished: pub divisions: UCL divisions: B02 divisions: D13 divisions: G23 note: This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode PubMed ID: 22972948 abstract: Background Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. Methods and results Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. Conclusions Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency. date: 2012-09 official_url: http://dx.doi.org/10.1136/jmedgenet-2012-101146 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_source: WoS-Lite elements_id: 787294 doi: 10.1136/jmedgenet-2012-101146 lyricists_name: Gissen, Paul lyricists_id: PGISS10 full_text_status: public publication: Journal of Medical Genetics volume: 49 number: 9 pagerange: 569 -577 issn: 0022-2593 citation: Alston, CL; Davison, JE; Meloni, F; van der Westhuizen, FH; He, L; Hornig-Do, H-T; Peet, AC; ... Taylor, RW; + view all <#> Alston, CL; Davison, JE; Meloni, F; van der Westhuizen, FH; He, L; Hornig-Do, H-T; Peet, AC; Gissen, P; Goffrini, P; Ferrero, I; Wassmer, E; McFarland, R; Taylor, RW; - view fewer <#> (2012) Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. Journal of Medical Genetics , 49 (9) 569 -577. 10.1136/jmedgenet-2012-101146 <https://doi.org/10.1136/jmedgenet-2012-101146>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1368873/1/Gissen_569.full.pdf