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